JP2018024685A - Natural combination hormone replacement formulations and therapies - Google Patents
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Abstract
Description
[関連出願の相互参照]
本出願は以下の米国仮特許出願:2011年11月23日出願の米国仮特許出願第61
/563,408号「天然複合ホルモン補充療法」;2012年6月18日出願の米国仮
特許出願第61/661,302号「エストラジオール製剤」;および2012年6月2
0日出願の米国仮特許出願第61/662,265号「プロゲステロン製剤」の優先権を
主張する。前述の出願はすべてその全開示を本明細書に参照により組み入れる。
[Cross-reference of related applications]
This application is based on the following US provisional patent application: US Provisional Patent Application No. 61 filed on November 23, 2011
No. 563,408 “Natural Combined Hormone Replacement Therapy”; US Provisional Patent Application No. 61 / 661,302 “Estradiol Formulation” filed June 18, 2012; and June 2, 2012
Claims priority of US Provisional Patent Application No. 61 / 662,265 “Progesterone Formulation” filed on Day 0. All of the aforementioned applications are hereby incorporated by reference in their entirety.
本開示は、それぞれ本明細書において以下で定義される、エストロゲンおよびプロゲス
テロン欠乏状態の治療に関する閉経前期、閉経周辺期、閉経期および閉経後期の女性の治
療のためにエストラジオールおよびプロゲステロンをそれぞれ単独でまたは組み合わせて
提供する製剤を用いる、天然エストロゲンおよびプロゲステロン補充療法に関する。
The present disclosure provides estradiol and progesterone, respectively, for the treatment of premenopausal, perimenopausal, menopausal and postmenopausal women, respectively, for the treatment of estrogen and progesterone deficiency, each as defined herein below. It relates to natural estrogen and progesterone replacement therapy using formulations provided in combination.
ホルモン補充療法(HRT)は、十分なホルモンが生成されない女性においてホルモン
レベルを増加させるように設計された薬剤の群の1つ以上の使用を含む医学的処置である
。HRTは、対象が閉経前期、閉経周辺期、閉経期または閉経後期であるかにかかわらず
、少なくなった循環エストロゲンおよびプロゲステロンホルモンにより引き起こされる症
状を鎮静および予防することができる。しかしながら、閉経期の各段階には特定の病態が
存在し得る。
Hormone replacement therapy (HRT) is a medical procedure that involves the use of one or more of a group of drugs designed to increase hormone levels in women who do not produce enough hormone. HRT can seduce and prevent symptoms caused by reduced circulating estrogen and progesterone hormones regardless of whether the subject is in premenopausal, perimenopausal, menopause, or late menopause. However, there may be specific pathologies at each stage of menopause.
HRTは現在さまざまな形態で利用可能である。1つの療法は低用量の1つ以上のエス
トロゲンの投与を含む。別の療法はプロゲステロンまたはプロゲスチンと呼ばれる化学類
似体の投与を含む。プロゲステロン投与は、他の病態を治療するとともに、例えば、子宮
内膜増殖症(肥厚)を含む、エストロゲン投与からの特定の望ましくない副作用を減少さ
せるように作用し、子宮内膜癌の発生率を低減する。
HRT is currently available in various forms. One therapy involves the administration of a low dose of one or more estrogens. Another therapy involves the administration of a chemical analog called progesterone or progestin. Progesterone administration treats other conditions and acts to reduce certain undesirable side effects from estrogen administration, including, for example, endometrial hyperplasia (thickening), thereby reducing the incidence of endometrial cancer To reduce.
用量投与のタイミングは周期的に変わることが多く、エストロゲンを毎日服用し、プロ
ゲステロンを毎月約2週間服用する方法は「周期間欠」または「間欠併用HRT」とよく
称される。この方法は自然な月経周期を模倣することを意図し、一般的にはプロゲステロ
ンが止まった後の月経と同様の月経を引き起こす。この処方計画は閉経周辺期または閉経
期に入ったばかりの女性においてもっとも一般的に用いられる。代替の連続方法ではこう
した女性において不正出血を引き起こすことが多いためである。エストロゲンおよびプロ
ゲステロンの両方を毎日一定用量服用する代替方法は「連続併用HRT」と呼ばれる。こ
の方法は通常は無月経を引き起こし、女性が閉経期に入ってしばらくした後に用いられる
ことがもっとも多い。
The timing of dose administration often changes periodically, and the method of taking estrogen daily and taking progesterone for about two weeks every month is often referred to as “cycle intermittent” or “intermittent HRT”. This method is intended to mimic the natural menstrual cycle and generally causes menstruation similar to that after progesterone ceases. This regimen is most commonly used in perimenopausal or just menopausal women. This is because alternative continuous methods often cause abnormal bleeding in these women. An alternative method of taking a fixed dose of both estrogen and progesterone daily is called “continuous combination HRT”. This method usually causes amenorrhea and is most often used after the woman has entered menopause for some time.
さまざまな形態のエストロゲン、およびさまざまな形態のプロゲステロンはHRTにお
いて、例えば、タブレット、カプセルおよびパッチを含む、さまざまな投与形態によって
用いられる。
Various forms of estrogen and various forms of progesterone are used in HRT by various dosage forms, including, for example, tablets, capsules and patches.
人体より自然に生成されるホルモンと化学構造が同等の「生物学的同等」ホルモンを用
いることができ、天然ホルモン補充療法、またはNHRTとよく称される。
“Biologically equivalent” hormones with chemical structures equivalent to those naturally occurring from the human body can be used, often referred to as natural hormone replacement therapy, or NHRT.
これらの天然または生物学的同等ホルモンはさまざまな成分から、エストラジオール、
エストロン、またはエストリオール(3つの主要なエストロゲン)および人体において自
然発生する(内因性)プロゲステロンの化学構造および効果と一致するように製剤される
。
These natural or bioequivalent hormones come from a variety of ingredients, including estradiol,
Formulated to be consistent with the chemical structure and effects of estrone, or estriol (three major estrogens) and naturally occurring (endogenous) progesterone in the human body.
現在、生物学的同等エストラジオールはブランドおよびジェネリック両方のFDA認可
バージョンで入手可能である。FDA認可のHRT用生物学的同等プロゲステロンは、プ
ロメトリウム(Prometrium;登録商標)(Abbott Laborator
ies、イリノイ州アボットパーク)として商業的に認識される単体ブランド薬、ならび
に開発者よりジェネリック認可された、Teva(イスラエル)およびSofgen A
mericas,Inc(ニューヨーク)より提供されるジェネリック製品として入手可
能である。プレンプロ(Prempro;登録商標)およびプレムフェーズ(Premp
hase;登録商標)(Pfizer,Inc.傘下のWyeth Laborator
ies、ニューヨーク)のような他の製品は、プレマリン(雌馬の尿由来のエストロゲン
)および合成メドロキシプロゲステロン酢酸エステルを含む連続併用および周期間欠製品
の両方を提供する。他の製品も入手可能である。しかしながら、生物学的同等エストラジ
オールおよび生物学的同等プロゲステロンの組み合わせを含むFDA認可製品は今日市場
に存在しない。
Currently, bioequivalent estradiol is available in both branded and generic FDA approved versions. FDA-approved bioequivalent progesterone for HRT is Promettrium® (Abbott Laborator).
ies, Abbott Park, Illinois), a single brand drug, and Teva (Israel) and Sofgen A, generically approved by the developer
It is available as a generic product provided by mericas, Inc (New York). Prempro (registered trademark) and prem phase (Prempro)
has; Wyeth Laboratories (Pfizer, Inc.)
Other products such as ies, New York) offer both continuous combination and periodic intermittent products including premarin (estrogens from mare urine) and synthetic medroxyprogesterone acetate. Other products are also available. However, there are no FDA approved products on the market today that contain a combination of bioequivalent estradiol and bioequivalent progesterone.
本開示の各種実施形態によると、可溶化エストラジオールならびに微粒子化および/ま
たは部分もしくは完全可溶化プロゲステロンの医薬製剤による周期間欠および連続併用投
与を含む天然ホルモン補充療法が提供される。毎日一緒に投与されるエストラジオールな
らびに微粒子化および/または部分もしくは完全可溶化プロゲステロンは、単一の単位用
量または別々の単位用量で、一般的にはソフトカプセル中に組み合わせることができる。
タブレットまたはカプセルの28日または1ヶ月の処方計画は、コンプライアンスを向上
するため投与日が記載された単一のブリスターパックに包装することができる。それぞれ
、天然ホルモン製剤、およびこれらの製剤のホルモン補充療法における使用のさまざまな
例を以下に記載する。
According to various embodiments of the present disclosure, natural hormone replacement therapy is provided, including periodic intermittent and continuous combined administration with solubilized estradiol and micronized and / or partially or fully solubilized progesterone pharmaceutical formulations. Estradiol and micronized and / or partially or fully solubilized progesterone administered together daily can be combined, typically in soft capsules, in a single unit dose or separate unit doses.
A 28 day or 1 month regimen of tablets or capsules can be packaged in a single blister pack with the date of administration listed to improve compliance. Various examples of natural hormone preparations and their use in hormone replacement therapy are described below, respectively.
本明細書に組み入れられ、本明細書の一部を形成する添付の図面は本開示について例示
し、本明細書とともにさらに本開示の原理を説明し、当業者が開示実施形態を製造および
使用することを可能にする。
しばしば、所定の病態を治療するには医薬品のより高い推奨経口投与用量が必要である
。多くの活性成分は治療が必要な患者に完全には吸収されないためである。換言すると、
例えば、プロゲステロンのような薬剤のより良く吸収される形態、または対象間での、単
独のもしくはエストラジオールと組み合わせたプロゲステロンの吸収のより良い一貫性を
提供する形態は、現在推奨されているものより低い有効性成分含量で投与することができ
、他の潜在的な利点とともに、副作用プロファイルの低減または最小化をもたらす可能性
がある。
Often, higher recommended oral dosages of pharmaceuticals are required to treat a given condition. This is because many active ingredients are not completely absorbed by patients in need of treatment. In other words,
For example, better absorbed forms of drugs such as progesterone, or forms that provide better consistency of absorption of progesterone, alone or in combination with estradiol, among subjects are lower than those currently recommended It can be administered at an active ingredient content and can lead to a reduction or minimization of the side effect profile, along with other potential benefits.
(定義)
「微粒子化プロゲステロン」の語は、本明細書において用いられる場合、約15ミクロ
ン未満のX50粒径値を有する、および/または約25ミクロン未満のX90粒径値を有
する微粒子化プロゲステロンを含む。
(Definition)
The term “micronized progesterone” as used herein includes micronized progesterone having an X50 particle size value less than about 15 microns and / or having an X90 particle size value less than about 25 microns.
「X50」の語は、本明細書において用いられる場合、試料中の粒子の1/2の直径が
所定の数より小さいことを意味する。例えば、5ミクロンのX50を有する微粒子化プロ
ゲステロンは、所定の微粒子化プロゲステロンの試料について、粒子の1/2が5ミクロ
ン未満の直径を有することを意味する。同様に、「X90」の語は、試料中の粒子の90
パーセント(%)の直径が所定の数より小さいことを意味する。
The term “X50” as used herein means that the diameter of one-half of the particles in the sample is less than a predetermined number. For example, micronized progesterone having an X50 of 5 microns means that for a given micronized progesterone sample, 1/2 of the particles have a diameter of less than 5 microns. Similarly, the term “X90” refers to 90 of the particles in the sample.
It means that the percentage (%) diameter is smaller than a predetermined number.
「中鎖」の語は、本明細書において用いられる場合、C4〜C18、とくにC6〜C1
2物質、グリセロールの脂肪酸エステル、脂肪酸、ならびにこうした物質のモノ、ジ、お
よびトリグリセリドを含む、いずれかの中鎖炭素含有物質を意味する。
The term “medium chain” as used herein refers to C4-C18, especially C6-C1.
Means any medium chain carbon containing material, including the two substances, fatty acid esters of glycerol, fatty acids, and mono, di, and triglycerides of such substances.
「均一分布」の語は、同様の有効性成分含量および同一のUSP溶解装置でプロメトリ
ウムと比較した溶解試験におけるプロゲステロンの均一な分散、可溶性、または凝集の欠
如の少なくとも1つを意味する。
The term “homogeneous distribution” means at least one of a similar active ingredient content and a uniform dispersion, solubility, or lack of aggregation of progesterone in a dissolution test compared to promethlium in the same USP dissolution apparatus.
「生物学的利用能」の語は、本明細書において用いられる場合、血液(血清または血漿
)中の活性成分(例えば、プロゲステロン、エストラジオールまたはエストロン)の濃度
を意味する。相対生物学的利用能は時間に対する血液(血清または血漿)中の濃度として
測定することができる。生物学的利用能を測定および評価するには、AUC、Cmax、
および任意でTmaxを含む適切なメトリクスにより割り出される他の薬物動態(pK)
指標を用いてもよい。
The term “bioavailability” as used herein means the concentration of an active ingredient (eg progesterone, estradiol or estrone) in the blood (serum or plasma). Relative bioavailability can be measured as the concentration in blood (serum or plasma) over time. To measure and assess bioavailability, AUC, C max ,
And optionally other pharmacokinetics (pK) determined by appropriate metrics including T max
An indicator may be used.
「AUC」の語は、本明細書において用いられる場合、時間経過に伴うプロゲステロン
、エストラジオールまたはエストロンの血中濃度の変化を表す曲線下領域を指す。
The term “AUC” as used herein refers to the area under the curve that represents the change in blood concentration of progesterone, estradiol, or estrone over time.
「Cmax」の語は、本明細書において用いられる場合、時間経過に伴うプロゲステロ
ン、エストラジオールまたはエストロンの血中濃度の変化を表す曲線上に示される血中濃
度の最大値を指す。
The term “C max ” as used herein refers to the maximum value of blood concentration shown on the curve representing the change in blood concentration of progesterone, estradiol or estrone over time.
「Tmax」の語は、本明細書において用いられる場合、プロゲステロン、エストラジ
オールまたはエストロン血中濃度が最大値に達するのにかかる時間を指す。
The term “T max ” as used herein refers to the time it takes for the progesterone, estradiol or estrone blood concentration to reach a maximum.
総括してAUC、Cmax、および任意でTmaxは、動物または人間の対象における
プロゲステロンのような特定の薬剤製品の薬物動態反応を特徴づけることができる主要な
薬物動態パラメータである。
Overall, AUC, C max , and optionally T max are key pharmacokinetic parameters that can characterize the pharmacokinetic response of a particular drug product, such as progesterone, in an animal or human subject.
「可溶化剤」の語は、本明細書において用いられる場合、例えば限定なしに、溶剤、共
溶剤、界面活性剤、乳化剤、油および担体のような、適切な医薬的に許容可能な付形剤を
含む、エストラジオールの可溶性を向上させるのに用いることができるいずれかの物質ま
たは物質の混合物を意味する。
The term “solubilizing agent” as used herein refers to suitable pharmaceutically acceptable excipients such as, without limitation, solvents, cosolvents, surfactants, emulsifiers, oils and carriers. By any substance or mixture of substances that can be used to improve the solubility of estradiol, including agents.
「付形剤」の語は、本明細書において用いられる場合、医薬製品の製剤に用いられる担
体、溶剤、油、潤滑剤等のような非活性医薬成分(「API」)物質を指す。それらは一
般的には、米国食品医薬品局より公表されているものを含む、構築された政府基準による
と、人間を含む動物への投与に安全である。
The term “shaped excipient” as used herein refers to an inactive pharmaceutical ingredient (“API”) substance such as a carrier, solvent, oil, lubricant, etc. used in the formulation of a pharmaceutical product. They are generally safe for administration to animals, including humans, according to established government standards, including those published by the US Food and Drug Administration.
「油」の語は、本明細書において用いられる場合、本明細書に記載されるような微粒子
化プロゲステロンを含む、いずれかの適切なプロゲステロン、出発材料、または前躯体を
懸濁および/または可溶化する、ピーナッツ油以外の、いずれかの医薬的に許容可能な物
質であってもよい。より具体的には、油は、例えば限定なしに、一般的には少なくとも1
つのモノ、ジ、およびトリグリセリド、これらの誘導体、またはこれらの組み合わせから
なる中鎖脂肪酸を含むことができる。
The term “oil”, as used herein, suspends and / or allows any suitable progesterone, starting material, or precursor, including micronized progesterone as described herein. It may be any pharmaceutically acceptable substance other than peanut oil that solubilizes. More specifically, the oil is generally at least 1 for example without limitation.
Medium chain fatty acids consisting of two mono-, di-, and triglycerides, derivatives thereof, or combinations thereof can be included.
「完全可溶化プロゲステロン」は、本明細書において用いられる場合、溶液中で約10
0%であるプロゲステロンを意味する。
“Completely solubilized progesterone” as used herein is about 10 in solution.
Means progesterone which is 0%.
「部分可溶化プロゲステロン」は、本明細書において用いられる場合、約100%未満
のいずれかの可溶化の状態であるプロゲステロンを意味する。
“Partially solubilized progesterone” as used herein means progesterone in any solubilized state of less than about 100%.
(説明)
本明細書では、以下の製剤:プロゲステロンを含まない可溶化エストラジオール;エス
トラジオールを含まない微粒子化プロゲステロン;部分可溶化プロゲステロンを含む微粒
子化プロゲステロン;微粒子化プロゲステロンを含む可溶化エストラジオール;部分可溶
化プロゲステロンと組み合わせた微粒子化プロゲステロンを含む可溶化エストラジオール
;および可溶化プロゲステロンを含む可溶化エストラジオールが提供される。本明細書に
おいて提供される根本的な製剤コンセプトは、他の天然または合成形態のエストラジオー
ルおよびプロゲステロンで用いてもよい。微粒子化の詳細、態様および実施形態を本明細
書においてさらに定義する。
(Description)
As used herein, the following formulations: solubilized estradiol without progesterone; micronized progesterone without estradiol; micronized progesterone with partially solubilized progesterone; solubilized estradiol with micronized progesterone; combined with partially solubilized progesterone Solubilized estradiol comprising micronized progesterone; and solubilized estradiol comprising solubilized progesterone are provided. The underlying formulation concept provided herein may be used with other natural or synthetic forms of estradiol and progesterone. Details, aspects and embodiments of micronization are further defined herein.
一般的には、本明細書に記載される医薬製剤は、充填カプセル、一般的には、例えば限
定なしに、ソフトゼラチンカプセルを含む、当技術分野において周知の1つ以上の材料の
ソフトカプセルとして調製および投与される。本明細書に記載されるような、微粒子化プ
ロゲステロンは、標準的な技術を用いてタブレットまたは他の周知の経口投与される投与
形態での投与用に調製することもできる。
In general, the pharmaceutical formulations described herein are prepared as filled capsules, generally soft capsules of one or more materials well known in the art, including, for example, without limitation, soft gelatin capsules. And administered. Micronized progesterone, as described herein, can also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques.
本開示の別の態様は、微粒子化プロゲステロン、部分可溶化プロゲステロンを含む微粒
子化プロゲステロンおよび完全可溶化プロゲステロンの医薬製剤を含み、前記製剤は治療
対象において、同等の有効性成分含量で投与される場合プロメトリウム(登録商標)によ
り提供される生物学的利用能と比較して増加したプロゲステロンの生物学的利用能を提供
することができる。
Another aspect of the present disclosure includes a pharmaceutical formulation of micronized progesterone, micronized progesterone comprising partially solubilized progesterone and fully solubilized progesterone, wherein said formulation is administered in a subject to be treated with an equivalent active ingredient content Progesterone bioavailability can be provided as compared to the bioavailability provided by Promethorium®.
各種態様および実施形態によると、可溶性割合(すなわち、溶液に入る溶質の割合)は
重要である。溶液全体の重量に対するエストラジオールの重量比も、本明細書において議
論される、意図する投与量のため重要である。とくに、カプセルによって容易に投与する
ことができるある量の溶液中のエストラジオールの標的用量を得ることが望ましい。例え
ば、カプセル中のエストラジオールの用量を約0.125mg〜約2mgとすることが望
ましい場合、約250mg〜約400mg、好適には約300mg〜約350mg、より
好適には約325mgの総溶液重量を有することも望ましい。各種実施形態では、総溶液
に対するエストラジオールの重量比は、約0.125:50mg〜約0.125:100
0mg、約1mg:500mg〜約1mg:50mg、約1mg:250mg〜約1mg
:60mg、約1mg:100mg〜約1mg:66mg、約2mg:50mg〜約2m
g:1000mgである。各種実施形態では、単回投与製品の標的は325mgであり、
複合製品(例えば、2つ以上のステロールAPI)の標的充填重量は650mgである。
According to various aspects and embodiments, the percentage of solubility (ie, the percentage of solute entering the solution) is important. The weight ratio of estradiol to the total solution weight is also important for the intended dosage discussed herein. In particular, it is desirable to obtain a target dose of estradiol in an amount of solution that can be easily administered by capsule. For example, if it is desired that the dose of estradiol in the capsule be from about 0.125 mg to about 2 mg, it has a total solution weight of about 250 mg to about 400 mg, preferably about 300 mg to about 350 mg, more preferably about 325 mg It is also desirable. In various embodiments, the weight ratio of estradiol to total solution is from about 0.125: 50 mg to about 0.125: 100.
0 mg, about 1 mg: 500 mg to about 1 mg: 50 mg, about 1 mg: 250 mg to about 1 mg
: 60 mg, about 1 mg: 100 mg to about 1 mg: 66 mg, about 2 mg: 50 mg to about 2 m
g: 1000 mg. In various embodiments, the target for a single dose product is 325 mg,
The target fill weight for composite products (eg, two or more sterol APIs) is 650 mg.
本開示の他の態様は、等用量のプロメトリウムと比較した場合、一般的には可溶化エス
トラジオールと組み合わせた、本開示のプロゲステロンの製剤におけるプロゲステロンの
より均一な溶解、ならびに患者内および患者間の血中濃度のばらつきの低減をさらに提供
する。血中濃度のばらつきは、投与後の同等のサンプリング時間でも比較される。理論に
より限定されるものではないが、これらの態様は各製剤中の可溶化プロゲステロンの割合
により影響されると考えられ、こうしたプロゲステロンのより均一な溶解、ならびにより
低い患者内および患者間の血中濃度のばらつきは、総プロゲステロンに対する可溶化プロ
ゲステロンのより大きな割合により影響される。プロゲステロンを含む本製剤は食効の低
減にも関係し得る。
Other aspects of the present disclosure include more uniform dissolution of progesterone in formulations of the presently disclosed progesterone, generally in combination with solubilized estradiol, and within and between patients, as compared to equal doses of promethorium It further provides a reduction in blood concentration variability. Variations in blood levels are also compared at equivalent sampling times after administration. Without being limited by theory, these aspects are believed to be affected by the proportion of solubilized progesterone in each formulation, and more uniform dissolution of such progesterone and lower blood levels within and between patients. Concentration variations are affected by a greater proportion of solubilized progesterone relative to total progesterone. This formulation containing progesterone may also be associated with reduced food effect.
同一のUSP装置を用いる同等の有効性成分含量のプロメトリウムの溶解と比較して本
開示の製剤中のプロゲステロンのより均一な溶解は、以下の実施例に記載されるものを含
む、API溶解試験用に構築された標準的な技術を用いて測定することができる。
More uniform dissolution of progesterone in the formulations of the present disclosure compared to dissolution of promethrium with an equivalent active ingredient content using the same USP device includes API dissolution tests, including those described in the examples below Can be measured using standard techniques built for.
プロメトリウムと比較して本開示に従って製剤されたプロゲステロンの患者内および患
者間のばらつきの低減は、以下に記載するもののような摂食バイオ実験によって示すこと
ができる。
Reduction of intra- and inter-patient variation of progesterone formulated according to the present disclosure compared to promethonium can be demonstrated by feeding bio experiments such as those described below.
本開示の他の態様は、それぞれ治療が必要な対象における、それぞれ非毒性で効果的な
量での、本明細書に記載されるような製剤であって、プロゲステロンが人間を含む動物の
:子宮内膜増殖症;続発性無月経;前記動物が短い子宮頸部を有する場合、早産;および
補充プロゲステロンで治療される他の病態または病状(総括して、「プロゲステロン欠乏
状態」)を治療するための前記製剤中の少なくとも1つのAPIである、製剤の使用、な
らびに本明細書に記載されるような製剤であって、エストラジオールが人間を含む動物の
:例えば、血管運動症状を含む閉経期関連症状;例えば限定なしに、顔面紅潮および寝汗
(血管運動症状)、睡眠障害、気分変動および外陰膣萎縮を含む、低エストロゲン症関連
症状;ならびに補充エストロゲンで治療される骨粗鬆症および他の非閉経期病態または症
状(総括して、「エストロゲン欠乏状態」)を治療するための前記製剤中の少なくとも1
つのAPIである、製剤の使用を含む。本明細書において用いられる場合、「治療」の語
、またはその派生語は、本明細書に記載されるような製剤が予防的に、またはこうした製
剤が投与される病態の発症後に投与される場合の記載される病態の部分または完全抑制と
考える。本開示の目的のため、「予防」とは、本明細書に記載される障害のいずれか、お
よびその他から動物を保護するための活性成分の動物への投与を指す。
Another aspect of the present disclosure is a formulation as described herein, each in a non-toxic and effective amount, each in a subject in need of treatment, wherein the progesterone is of an animal including a human: uterus To treat endometrial hyperplasia; secondary amenorrhea; premature birth if the animal has a short cervix; and other conditions or conditions treated with supplemental progesterone (collectively “progesterone deficiency”) Use of a formulation that is at least one API in said formulation, as well as a formulation as described herein, wherein estradiol is an animal including a human: for example menopausal related symptoms including vasomotor symptoms Hypoestrogen-related symptoms, including, for example, without limitation, flushing and night sweats (vasomotor symptoms), sleep disorders, mood swings and vulva vaginal atrophy; and supplemental estrogens In (and collectively, "Estrogen deficiency states") osteoporosis, and other non-menopausal condition or symptoms being treated at least in the formulation to treat
Including the use of formulations, one API. As used herein, the term “treatment” or derivative thereof is used when a formulation as described herein is administered prophylactically or after the onset of a condition for which such formulation is administered. Considered as part of the described pathology or complete suppression. For the purposes of this disclosure, “prevention” refers to the administration of an active ingredient to an animal to protect the animal from any of the disorders described herein, and others.
とくに指定のない限り、「天然」とは、本明細書において本明細書で議論されるホルモ
ンを指して用いられる場合、人体において自然発生する(内因性の)ものの化学構造およ
び効果と一致するように製剤される生物学的同等ホルモンを意味する。例となる天然エス
トロゲンはエストラジオール(17β−エストラジオールおよびE2とも記載される)で
あり、天然プロゲスチンはプロゲステロンである。例となる周期/間欠処方計画は、14
〜18日間毎日約0.125mg〜約2.0mgのエストラジオールの投与、ならびにそ
の後10〜14日間毎日約0.125mg〜約2mgのエストラジオールおよび約25m
g〜約200mgのプロゲステロンの投与を含む。周期/間欠処方計画は閉経期の女性に
特に有用であり得る。本明細書に記載される製剤において用いられるエストラジオールの
他の例となる有効性成分含量としては、限定なしに、0.125、0.25、0.375
、0.50、0.625、0.75、1.00、1.125、1.25、1.375、1
.50、1.625、1.75および2.00mgが挙げられる。本明細書に記載される
製剤において用いられるプロゲステロンの他の例となる有効性成分含量としては、限定な
しに、25、50、75、100、125、150、175、200、250、300、
350および400mgが挙げられる。エストラジオールおよびプロゲステロンそれぞれ
のこれらの有効性成分含量は、本明細書に記載される製剤で単独でまたは組み合わせて投
与することができる。
Unless otherwise specified, “natural” as used herein to refer to the hormones discussed herein is consistent with the chemical structure and effects of those naturally occurring in the human body (endogenous). Means a bioequivalent hormone formulated in An exemplary natural estrogen is estradiol (also described as 17β-estradiol and E2) and the natural progestin is progesterone. An exemplary periodic / intermittent prescription plan is 14
Administration of about 0.125 mg to about 2.0 mg estradiol daily for -18 days, and about 0.125 mg to about 2 mg estradiol and about 25 m daily for 10-14 days thereafter
Includes administration of g to about 200 mg of progesterone. Cycle / intermittent regimens can be particularly useful for menopausal women. Other exemplary active ingredient contents used in the formulations described herein include, without limitation, 0.125, 0.25, 0.375.
0.50, 0.625, 0.75, 1.00, 1.125, 1.25, 1.375, 1
. 50, 1.625, 1.75 and 2.00 mg. Other exemplary active ingredient content used in the formulations described herein include, without limitation, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300,
350 and 400 mg are mentioned. These active ingredient contents of each of estradiol and progesterone can be administered alone or in combination in the formulations described herein.
プロゲステロン活性医薬成分は、当業者により一般的に用いられる複数の方法のいずれ
か1つによって微粒子化することができる。各種実施形態では、微粒子化プロゲステロン
は約15ミクロン未満、約10ミクロン未満、約5ミクロン未満、および/または約3ミ
クロン未満のX50粒径値を有する。各種実施形態では、微粒子化プロゲステロンは約2
5ミクロン未満、約20ミクロン未満、および/または約15ミクロン未満のX90粒径
値を有する。
The progesterone active pharmaceutical ingredient can be microparticulated by any one of a number of methods commonly used by those skilled in the art. In various embodiments, micronized progesterone has an X50 particle size value of less than about 15 microns, less than about 10 microns, less than about 5 microns, and / or less than about 3 microns. In various embodiments, the micronized progesterone is about 2
It has an X90 particle size value of less than 5 microns, less than about 20 microns, and / or less than about 15 microns.
粒径はいずれかの適切な方法で測定することができる。例えば、ベックマン・コールタ
ーLS13320レーザー回析式粒度分布測定装置(「ベックマン装置」)を用いて粒径
を測定することができる。上述したように、粒径は各種メトリクス、例えば、X50粒径
、および/もしくはX90粒径、または同様の粒径の記載により表すことができる。
The particle size can be measured by any suitable method. For example, the particle size can be measured using a Beckman Coulter LS13320 laser diffraction particle size distribution measuring device (“Beckman device”). As noted above, particle size can be represented by a description of various metrics, such as X50 particle size and / or X90 particle size, or similar particle sizes.
ベックマン装置は分析用の試料を導入するためのさまざまなモジュールとともに用いる
ことができる。ベックマン装置はLS13320ユニバーサルリキッドモジュール(「U
LM」)とともに用いることができる。ULMは0.017μm〜2000μmのサイズ
範囲内の試料を懸濁させることができる。ULMは試料を感知ゾーンへ送達することがで
きる液体ベースのモジュールである。ULMは試料をベックマン装置中に再循環させる。
ULMは2つのホース、液体送達用の1つと排出用のもう1つを備える。用いられる総体
積は125mL以下であり得る。約1mg〜約10gの試料質量を用いることができる。
ULMは、ULM上のスロットに取り付けられたピンによってベックマン装置と相互作用
することができる。ULMはさまざまな懸濁液、例えば、水、ブタノール、エタノール、
クロロホルム、ヘプタン、トルエン、プロパノール、コールター1Bタイプ分散剤(「コ
ールター1B」)、およびさまざまな他の懸濁液を用いることができる。界面活性剤を用
いることもできるが、ポンプ速度は過剰なバブリングを抑制するように調節されるべきで
ある。コールター1Bはアセトアルデヒド、エチレンオキシド、および/または1,4−
ジオキサンの1つ以上を含むことができる。ベックマン装置は、フラウンホーファー光学
モデルおよびミー理論を含む、さまざまな光学理論を用いるように構成することができる
。
The Beckman device can be used with various modules for introducing samples for analysis. The Beckman device is a LS13320 universal liquid module ("U
LM "). The ULM can suspend samples in the size range of 0.017 μm to 2000 μm. The ULM is a liquid-based module that can deliver a sample to the sensing zone. The ULM recirculates the sample through the Beckman device.
The ULM has two hoses, one for liquid delivery and another for drainage. The total volume used can be 125 mL or less. A sample mass of about 1 mg to about 10 g can be used.
The ULM can interact with the Beckman device by pins attached to slots on the ULM. ULM is available in various suspensions such as water, butanol, ethanol,
Chloroform, heptane, toluene, propanol, Coulter 1B type dispersant (“Coulter 1B”), and various other suspensions can be used. Surfactants can also be used, but the pump speed should be adjusted to suppress excessive bubbling. Coulter 1B is acetaldehyde, ethylene oxide, and / or 1,4-
One or more of dioxane can be included. The Beckman device can be configured to use a variety of optical theories, including Fraunhofer optical models and Mie theory.
ベックマン装置はULMの使用中にベックマン装置を制御するためのソフトウェアを備
えることができる。ソフトウェアは、例えば特に、ポンプ速度、気泡除去手順、洗い流し
手順、超音波処理手順、および充填手順の使用を制御することができる。試料分析に関す
るパラメータを構成することもできる。例えば、分析時間を設定することができる。いず
れかの適切な分析時間を用いることができるが、各種実施形態では、30秒〜120秒、
好適には30秒〜90秒の時間を用いることができる。
The Beckman device can include software for controlling the Beckman device during use of the ULM. The software can control, for example, the use of pump speeds, bubble removal procedures, flushing procedures, sonication procedures, and filling procedures, among others. Parameters related to sample analysis can also be configured. For example, the analysis time can be set. Any suitable analysis time can be used, but in various embodiments, 30 seconds to 120 seconds,
A time of 30 seconds to 90 seconds can be preferably used.
ベックマン装置はLS13320マイクロリキッドモジュール(「MLM」)とともに
用いることができる。MLMは0.4μm〜2000μmのサイズ範囲内の試料を懸濁さ
せることができる。MLMは試料を感知ゾーンへ送達することができる液体ベースのモジ
ュールである。MLMは撹拌器を備える。用いられる総体積は12mL以下であり得る。
MLMは、水性および非水性両方の、さまざまな懸濁液を用いることができる。
The Beckman device can be used with the LS13320 micro liquid module ("MLM"). The MLM can suspend samples in the size range of 0.4 μm to 2000 μm. An MLM is a liquid-based module that can deliver a sample to a sensing zone. The MLM is equipped with a stirrer. The total volume used can be 12 mL or less.
MLM can use a variety of suspensions, both aqueous and non-aqueous.
本明細書に記載されるようなエストラジオールおよびプロゲステロンのそれぞれは、以
下の教示に従って単独で製剤することができる。これらの製剤は経口投与用に調製するこ
とができ、または相溶性に基づき、単一経口単位投与形態でのエストラジオールおよびプ
ロゲステロンの共投与用に組み合わせることができる。
Each of estradiol and progesterone as described herein can be formulated alone according to the following teachings. These formulations can be prepared for oral administration or can be combined for co-administration of estradiol and progesterone in a single oral unit dosage form based on compatibility.
本開示のプロゲステロン製剤は医薬的に許容可能な油とのブレンドによって調製され、
一般的には、油は少なくとも1つの中鎖脂肪酸、例えば少なくとも1つのモノ、ジ、もし
くはトリグリセリド、これらの誘導体、またはこれらの組み合わせからなる中鎖脂肪酸を
含む。例えば、限定なしに抗酸化剤、潤滑剤等を含む、他の付形剤が任意で添加される。
微粒子化プロゲステロンの懸濁液を形成、または代替ではプロゲステロンを可溶化するの
に十分な油が用いられる。
The progesterone formulations of the present disclosure are prepared by blending with a pharmaceutically acceptable oil,
Generally, the oil comprises at least one medium chain fatty acid, such as at least one mono, di, or triglyceride, derivatives thereof, or combinations thereof. Other shaping agents are optionally added including, for example, without limitation, antioxidants, lubricants, and the like.
Sufficient oil is used to form a suspension of micronized progesterone, or alternatively solubilize the progesterone.
医薬的に許容可能な油は、限定なしに、カプロン脂肪酸;カプリル脂肪酸;カプリン脂
肪酸;タウリン酸;ミリスチン酸;リノール酸;コハク酸;グリセリン;モノ、ジ、また
はトリグリセリド、これらの組み合わせおよび誘導体;ポリエチレングリコール;ポリエ
チレングリコールグリセリド(ゲルシール(Gelucire;登録商標);GATTE
FOSSE SAS、サン−プリースト、フランス);プロピレングリコール;カプリル
酸/カプリン酸トリグリセリド(ミグリオール(Miglyol;登録商標);SASO
L Germany GMBH、ハンブルグ;ミグリオールとしてはミグリオール810
、812、816および829が挙げられる);カプロン酸/カプリル酸/カプリン酸/
ラウリン酸トリグリセリド;カプリル酸/カプリン酸/リノール酸トリグリセリド;カプ
リル酸/カプリン酸/コハク酸トリグリセリド;プロピレングリコールモノカプリレート
;プロピレングリコールモノカプレート:(キャプムル(Capmul;登録商標)PG
−8および10;キャプムルブランドはABITEC、オハイオ州コロンバスが所有);
プロピレングリコールジカプリレート;プロピレングリコールジカプリレート;中鎖モノ
およびジグリセリド(キャプムルMCM);ジエチレングリコールモノエステル(2−(
2−エトキシエトキシ)エタノール;トランスクトール(Transcutol)を含む
);ジエチレングリコールモノエチル;飽和ココナッツおよびパーム核油のエステルおよ
びこれらの誘導体;分留植物脂肪酸のトリグリセリド、これらの組み合わせおよび誘導体
の少なくとも1つの使用を含む。
Pharmaceutically acceptable oils include, without limitation, caprolic fatty acids; capryl fatty acids; capric fatty acids; tauric acid; myristic acid; linoleic acid; succinic acid; glycerin; mono, di, or triglycerides, combinations and derivatives thereof; Glycol; Polyethylene glycol glyceride (Gelucire®); GATTE
FOSSE SAS, Saint-Priest, France); propylene glycol; caprylic / capric triglycerides (Miglyol®); SASO
L Germany GMBH, Hamburg;
, 812, 816 and 829); caproic acid / caprylic acid / capric acid /
Lauric acid triglyceride; caprylic acid / capric acid / linoleic acid triglyceride; caprylic acid / capric acid / succinic acid triglyceride; propylene glycol monocaprylate; propylene glycol monocaprate: (Capmul® PG
-8 and 10; Capmul brand is owned by ABITEC, Columbus, Ohio);
Propylene glycol dicaprylate; propylene glycol dicaprylate; medium chain mono- and diglycerides (Capmul MCM); diethylene glycol monoester (2- (
2-ethoxyethoxy) ethanol; including transcutol); diethylene glycol monoethyl; esters of saturated coconut and palm kernel oils and derivatives thereof; use of at least one of triglycerides of fractionated plant fatty acids, combinations and derivatives thereof including.
他の態様および実施形態では、プロゲステロンは、例えば限定なしに、十分な量の:ト
ランスクトールおよびミグリオール;トランスクトール、ミグリオール、キャプムルPG
8および/またはPG10;キャプムルMCM;キャプムルMCMおよび非イオン性界面
活性剤;ならびにキャプムルMCMおよびゲルシールを用いて完全に可溶化される。
In other aspects and embodiments, the progesterone is, for example, without limitation, a sufficient amount of: transcutol and miglycol; transcutol, miglycol, capmul PG.
8 and / or PG10; Capmul MCM; Capmul MCM and nonionic surfactant; and Capmul MCM and gel seals are used to fully solubilize.
これらの油のさまざまな比をプロゲステロンの完全可溶化に用いることができる。キャ
プムルMCMおよび非イオン性界面活性剤は、例えば限定なしに:65:35、70:3
0、75:25、80:20、85:15および90:10を含む比で用いることができ
る。キャプムルMCMおよびゲルシールは、例えば限定なしに、6:4、7:3、8:2
および9:1を含む比で用いることができる。他の組み合わせとともに、本明細書におい
て定義されるような、これらの油および/または可溶化剤、ならびにこれらの組み合わせ
を用い、本開示のエストラジオールおよびプロゲステロンの複合製剤を形成することがで
きる。
Various ratios of these oils can be used for complete solubilization of progesterone. Capmul MCM and nonionic surfactants include, for example, without limitation: 65:35, 70: 3
It can be used in ratios including 0, 75:25, 80:20, 85:15 and 90:10. Capmul MCM and gel seals are, for example, without limitation, 6: 4, 7: 3, 8: 2.
And ratios including 9: 1. These oils and / or solubilizers, and combinations thereof, as defined herein, along with other combinations, can be used to form a combined formulation of estradiol and progesterone of the present disclosure.
これらの油の組み合わせは、プロゲステロンの所望の単位用量に応じて、部分可溶化プ
ロゲステロンを生成することができる。単位投与形態当たりのプロゲステロンの量が多い
ほど、より少ないプロゲステロンが可溶化され得る。単位用量当たりの有効性成分含量の
上限は、一般的には最終投与形態の実際のサイズによってのみ制限される。
These oil combinations can produce partially solubilized progesterone, depending on the desired unit dose of progesterone. The greater the amount of progesterone per unit dosage form, the less progesterone can be solubilized. The upper limit of active ingredient content per unit dose is generally limited only by the actual size of the final dosage form.
各種実施形態では、エストラジオールは部分的に、実質的に、または完全に可溶化され
る。可溶化エストラジオールは、溶剤中で約:90%可溶性;93%可溶性;95%可溶
性;97%可溶性;99%可溶性;および100%可溶性であるエストラジオールを含む
ことができる。可溶性は質量画分(%w/w)として表すことができる。
In various embodiments, estradiol is partially, substantially, or completely solubilized. Solubilized estradiol can include estradiol that is about: 90% soluble; 93% soluble; 95% soluble; 97% soluble; 99% soluble; and 100% soluble in a solvent. Solubility can be expressed as a mass fraction (% w / w).
各種実施形態では、可溶化剤は溶剤または共溶剤の少なくとも1つから選択される。適
切な溶剤および共溶剤としては、いずれかのモノ、ジまたはトリグリセリドおよびグリコ
ール、ならびにこれらの組み合わせが挙げられる。
In various embodiments, the solubilizer is selected from at least one of a solvent or a co-solvent. Suitable solvents and co-solvents include any mono, di or triglyceride and glycol, and combinations thereof.
エストラジオールの可溶化剤として用いることもできる、プロゲステロンについて上で
参照した油に加えて、他の可溶化剤としては、例えば限定なしに、グリセリルモノおよび
ジカプリレート、プロピレングリコールならびに1,2,3−プロパントリオール(グリ
セロール、グリセリン、グリセリン)が挙げられる。
In addition to the oils referred to above for progesterone, which can also be used as a solubilizer for estradiol, other solubilizers include, but are not limited to, glyceryl mono and dicaprylate, propylene glycol and 1,2,3-propane. And triols (glycerol, glycerin, glycerin).
エストラジオール、プロゲステロンまたはこれらの組み合わせを含有する現在開示され
ている製剤の他の実施形態では、アニオン性および/または非イオン性界面活性剤を用い
ることができる。特定の実施形態では、非イオン性界面活性剤が用いられる。例となる非
イオン性界面活性剤としては、例えば限定なしに、オレイン酸、リノール酸、パルミチン
酸、およびステアリン酸の1つ以上を挙げることができる。さらなる実施形態では、非イ
オン性界面活性剤としては、商標トゥイーン(TWEEN)80(登録商標)で市販され
るポリソルベート80(Sigma Aldrich、ミズーリ州セントルイス)を含む
、ポリエチレンソルビトールエステルを挙げることができる。ポリソルベート80は約6
0%〜70%のオレイン酸を含み、残部は主にリノール酸、パルミチン酸、およびステア
リン酸を含む。ポリソルベート80は製剤総質量の約5〜50%の範囲内、特定の実施形
態では約30%の量で用いることができる。
In other embodiments of the presently disclosed formulations containing estradiol, progesterone or combinations thereof, anionic and / or nonionic surfactants can be used. In certain embodiments, nonionic surfactants are used. Exemplary nonionic surfactants can include, for example, without limitation, one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid. In a further embodiment, the nonionic surfactant can include a polyethylene sorbitol ester, including polysorbate 80 (Sigma Aldrich, St. Louis, Mo.) marketed under the trademark TWEEN 80®. Polysorbate 80 is about 6
Contains 0% to 70% oleic acid, with the balance mainly containing linoleic acid, palmitic acid, and stearic acid. Polysorbate 80 can be used in an amount in the range of about 5-50% of the total formulation weight, and in certain embodiments, about 30%.
さまざまな他の実施形態では、非イオン性界面活性剤は、長鎖脂肪酸のグリセロールお
よびポリエチレングリコールエステル、例えば、例えばゲルシール44/11およびゲル
シール44/14を含む、ゲルシールとして市販される、ラウロイルマクロゴール−32
グリセリド、および/またはラウロイルポリオキシル−32グリセリドの1つ以上から選
択される。これらの界面活性剤は約0.01%より高い濃度で、一般的には約0.01%
〜10.0%、10.1%〜20%、および20.1%〜30%のさまざまな量で用いる
ことができる。
In various other embodiments, the nonionic surfactants are glycerol and polyethylene glycol esters of long chain fatty acids, such as lauroyl macrogol, marketed as gel seals, including, for example, gel seal 44/11 and gel seal 44/14. -32
It is selected from one or more of glycerides and / or lauroyl polyoxyl-32 glycerides. These surfactants are in concentrations above about 0.01%, typically about 0.01%
It can be used in various amounts of ˜10.0%, 10.1% to 20%, and 20.1% to 30%.
他の実施形態では、潤滑剤が用いられる。例えばレシチンのような、いずれかの適切な
潤滑剤を用いることができる。レシチンはリン脂質の混合物を含むことができる。
In other embodiments, a lubricant is used. Any suitable lubricant, such as lecithin, can be used. Lecithin can comprise a mixture of phospholipids.
さらなる実施形態では、抗酸化剤が用いられる。例えば限定なしにブチル化ヒドロキシ
トルエンのような、いずれかの適切な抗酸化剤を用いることができる。
In a further embodiment, an antioxidant is used. Any suitable antioxidant can be used, such as butylated hydroxytoluene without limitation.
例えば、各種実施形態では、医薬製剤は、約20重量%〜約80重量%の担体、約0.
1重量%〜約5重量%の潤滑剤、および約0.01重量%〜約0.1重量%の抗酸化剤を
含む。
For example, in various embodiments, the pharmaceutical formulation comprises from about 20% to about 80% by weight carrier, about 0.1%.
1% to about 5% by weight lubricant, and about 0.01% to about 0.1% by weight antioxidant.
付形剤の選択は、特定の投与モード、付形剤の可溶性および安定性に対する効果、なら
びに投与形態の性質のような要素に大きく左右される。各種実施形態に用いられる付形剤
としては、着色剤、着香剤、防腐剤および矯味剤を挙げることができる。着色剤は、例え
ば、約0.1重量%〜約2重量%で含むことができる。防腐剤はメチルおよびプロピルパ
ラベンを、例えば、約10:1の比で、および約0.005重量%〜0.05重量%の割
合で含むことができる。
The choice of excipient is highly dependent on factors such as the particular mode of administration, the effect on excipient solubility and stability, and the nature of the dosage form. Examples of the shaping agent used in various embodiments include a coloring agent, a flavoring agent, a preservative, and a corrigent. The colorant can include, for example, from about 0.1% to about 2% by weight. The preservative can include methyl and propylparaben, for example, in a ratio of about 10: 1 and in a ratio of about 0.005 wt% to 0.05 wt%.
本明細書に記載される製剤において用いられるすべての油、可溶化剤、付形剤およびそ
の他の添加剤は同様に、それぞれ非毒性および医薬的に許容可能でなければならない。
All oils, solubilizers, excipients and other additives used in the formulations described herein must also be non-toxic and pharmaceutically acceptable, respectively.
上記で参照したように、本開示の製剤は通常、一般的には、例えば、ソフトカプセルの
ようなカプセルによって、経口投与される。本製剤を用い、当技術分野において知られる
標準的な技術を用いて経皮パッチを形成することもできる。本発明の可溶化製剤は、当技
術分野において周知の技術を用いて腹腔内投与用に製剤することもできる。
As referred to above, the formulations of the present disclosure are typically administered orally, for example by capsules such as soft capsules. The formulation can also be used to form transdermal patches using standard techniques known in the art. The solubilized formulations of the present invention can also be formulated for intraperitoneal administration using techniques well known in the art.
各種実施形態によると、製剤はピーナッツ油を含まない。ピーナッツ油を含まないこと
でピーナッツ系アレルギーを有する対象が負うリスクを排除する。
According to various embodiments, the formulation does not include peanut oil. The absence of peanut oil eliminates the risk posed to subjects with peanut allergies.
本明細書に記載される各種実施形態によると、カプセルの28日または1ヶ月の処方計
画は、とりわけ、コンプライアンスを向上し、関連症状を低減するため、投与日を記載し
た単一のキット(例えば、ブリスターパック)に包装することができる。カプセルの1つ
以上は、例えば、エストラジオールおよび/またはプロゲステロンを含有しない場合があ
り得る。エストロゲンまたはプロゲステロンAPIを含まないカプセルはプラセボと称す
ることができる。ブリスターパックはブリスターパックを28日に分ける複数の切り込み
または切り取り線を有することができる。各日の単一のブリスターまたは複数のブリスタ
ーをさらに含むことができる。各種実施形態では、各単位用量は微粒子化、部分可溶化も
しくは完全可溶化プロゲステロンおよび/または可溶化エストラジオールを本明細書にお
いて上述した量で含有してもよいが、他の用量範囲を考慮してもよい。加えて、本明細書
では他の構成を有するキットも考慮される。例えば、限定なしに、こうしたブリスターパ
ックを有するキットはいくつかのカプセルを含有することができる。
According to various embodiments described herein, a 28-day or 1-month regimen of capsules, among other things, a single kit that describes the date of administration (eg, to improve compliance and reduce associated symptoms) , Blister pack). One or more of the capsules may not contain estradiol and / or progesterone, for example. Capsules that do not contain estrogen or progesterone API can be referred to as placebos. The blister pack can have multiple cuts or tear lines that divide the blister pack into 28 days. It can further include a single blister or multiple blisters for each day. In various embodiments, each unit dose may contain micronized, partially solubilized or fully solubilized progesterone and / or solubilized estradiol in the amounts described herein above, but other dose ranges are considered. Also good. In addition, kits having other configurations are also contemplated herein. For example, without limitation, a kit with such blister packs can contain several capsules.
微粒子化および/または部分可溶化もしくは完全可溶化プロゲステロンを含有する本開
示の経口投与製剤は、子宮内膜増殖症、続発性無月経および補充プロゲステロンで治療さ
れる他の病態の治療にも用いられる。一般的には、本明細書に記載されるプロゲステロン
含有製剤は、単独でまたは本開示の可溶化エストラジオールもしくは他のエストロゲン含
有製剤と組み合わせて投与されるかにかかわらず、補充エストロゲンの投与の効果に対処
するのに用いられる。さまざまな他の実施形態では、本開示の製剤を含有するカプセル、
例えばソフトゲルカプセルは膣中または周りに適用することができる。
Orally administered formulations of the present disclosure containing micronized and / or partially solubilized or fully solubilized progesterone can also be used to treat endometrial hyperplasia, secondary amenorrhea and other conditions treated with supplemented progesterone . In general, the progesterone-containing formulations described herein are effective in administering supplemented estrogens, whether administered alone or in combination with the solubilized estradiol or other estrogen-containing formulations of the present disclosure. Used to deal with. In various other embodiments, a capsule containing a formulation of the present disclosure,
For example, soft gel capsules can be applied in or around the vagina.
可溶化エストラジオールを含有する本開示の製剤は、例えば、血管運動症状、例えば限
定なしに、顔面紅潮および寝汗(血管運動症状)、睡眠障害、気分変動、外陰膣萎縮を含
む低エストロゲン症関連症状、ならびに骨粗鬆症および補充エストロゲンで治療される他
の非閉経期病態を含む、エストロゲン欠乏状態を治療するのに用いられる。
Formulations of the present disclosure containing solubilized estradiol include, for example, vasomotor symptoms, such as, without limitation, facial flushing and night sweats (vasomotor symptoms), sleep disorders, mood swings, hypoestrogen related symptoms including vulva vaginal atrophy, And used to treat estrogen deficiency conditions, including osteoporosis and other non-menopausal conditions treated with supplemental estrogens.
可溶化エストラジオールを含有する本開示の製剤は、萎縮性膣炎または外陰膣萎縮を治
療または予防するのに用いることができる。各種実施形態では、カプセル、例えばソフト
ゲルカプセルを膣中または周りに適用することができる。
The formulations of the present disclosure containing solubilized estradiol can be used to treat or prevent atrophic vaginitis or vulvovaginal atrophy. In various embodiments, capsules, such as soft gel capsules, can be applied in or around the vagina.
本開示のさらなる目的としては、使いやすさによる患者コンプライアンスの向上;使用
方法のわかりやすさと不適切な使用による副作用の心配の少なさによる医師採用の増加;
誤用による副作用の減少(不正出血の減少);適切な使用による症状のより良好な効能制
御;一般的に用いられる合成プロゲスチンの、単独でまたはエストロゲン(ノルエチンド
ロン酢酸エステル、メドロキシプロゲステロン酢酸エステル、等)と組み合わせて投与さ
れる場合の、例えば、脳卒中、心臓発作、血栓および乳癌を含む、代謝および血管副作用
の低減の提供が挙げられる。
Further objectives of this disclosure include improved patient compliance through ease of use; increased physician adoption due to ease of use and less concern about side effects due to inappropriate use;
Reduced side effects due to misuse (reduced abnormal bleeding); better control of symptoms with proper use; commonly used synthetic progestins, alone or estrogens (norethindrone acetate, medroxyprogesterone acetate, etc.) For example, providing reduction of metabolic and vascular side effects, including, for example, stroke, heart attack, thrombus and breast cancer.
(実施例1:エストラジオール可溶性)
各種実験では、所望の目標をエストラジオールについて〜20mg/gの可溶性を達成
することとし、100mgの充填物質中2mgをエストラジオールとするのに十分な可溶
性を提供するために適切な溶剤を決定した。エストラジオールを各種溶剤と混合し、溶液
をエストラジオールで飽和し、少なくとも3日間平衡化し、未溶解粒子を濾過し、HPL
Cによりエストラジオールの溶解量について透明な浮遊物を分析することにより、初期可
溶性実験を行った。
(Example 1: Estradiol soluble)
In various experiments, the desired goal was to achieve a solubility of ˜20 mg / g for estradiol and the appropriate solvent was determined to provide sufficient solubility to make 2 mg of estradiol in 100 mg of packing material. Estradiol is mixed with various solvents, the solution is saturated with estradiol, equilibrated for at least 3 days, undissolved particles are filtered, HPL
Initial solubility experiments were performed by analyzing clear suspensions for dissolved amount of estradiol by C.
エストラジオール可溶性実験を行った。この表から、少なくとも1つの品目(例えばプ
ロピレングリコール)はカプセル化には適さないことがわかる。
Estradiol solubility experiments were performed. From this table it can be seen that at least one item (eg propylene glycol) is not suitable for encapsulation.
(実施例2)
200mgの総カプセル充填物質中2mgのエストラジオールを可溶化することもでき
る媒体中での50mgのプロゲステロンの懸濁を達成することが望ましかった。この製剤
を達成するため、必要なエストラジオールの可溶性は〜10mg/gでなければらない。
200mgの総充填重量はサイズ5の楕円形ソフトゼラチンカプセルに適していると考え
られた。
(Example 2)
It was desirable to achieve a suspension of 50 mg progesterone in a medium that could also solubilize 2 mg estradiol in 200 mg total capsule fill material. In order to achieve this formulation, the required estradiol solubility should be -10 mg / g.
A total fill weight of 200 mg was considered suitable for size 5 oval soft gelatin capsules.
ソフトゼラチンカプセル化により適している可能性のある溶剤混合物を見出すため、さ
らなる可溶性実験を行った。可溶性実験は、キャプムルPG8およびキャプムルMCMを
用い、エストラジオールを各種溶剤システムと混合し、前と同様に濾過後HPLCにより
エストラジオールの溶解量について分析することにより行った。これらの実験の結果を表
2に示す。これらの結果から、50%のミグリオール:キャプムルPG8;およびまた単
独のまたは20%のポリソルベート80と組み合わせたキャプムルMCMを含有する混合
物が、10mg/gの標的を満たすのに十分な可溶性を達成することができることは明ら
かである。15および30%濃度でミグリオールと混合したキャプムルPG8は十分な可
溶性を提供しなかった。
Additional solubility experiments were performed to find solvent mixtures that may be more suitable for soft gelatin encapsulation. The solubility experiment was conducted by using Capmul PG8 and Capmul MCM, mixing estradiol with various solvent systems, and analyzing the amount of estradiol dissolved by HPLC after filtration as before. The results of these experiments are shown in Table 2. From these results, a mixture containing 50% Miglyol: Capmul PG8; and also Capmul MCM alone or in combination with 20% polysorbate 80 achieves sufficient solubility to meet a target of 10 mg / g. Obviously you can. Capmul PG8 mixed with miglyol at 15 and 30% concentrations did not provide sufficient solubility.
(実施例3)
さらなる実験を行い、表3に報告するように、溶剤混合物中のエストラジオール(4〜
6mg)の安定性を評価した。4%のトランスクトールを有するミグリオール812は温
/冷サイクルで96時間後に沈殿したが、30および50%のミグリオール:キャプムル
のブレンド中、または単独のキャプムルMCM中に可溶化させたエストラジオールは、同
じ条件下で少なくとも14日間沈殿しなかった。
(Example 3)
Further experiments were performed and, as reported in Table 3, estradiol (4 to 4) in the solvent mixture.
6 mg) was evaluated. Miglyol 812 with 4% transcutol precipitated after 96 hours in a warm / cold cycle, but estradiol solubilized in 30 and 50% miglycol: Capmul blends or in Capumle MCM alone was under the same conditions. Did not precipitate for at least 14 days.
50:50のミグリオール:キャプムルPG8、キャプムルMCM、およびトランスク
トール:ミグリオール:キャプムルPG8の混合物中に可溶化させた12mgのエストラ
ジオールは安定であり、少なくとも12日間沈殿しない。
12 mg of estradiol solubilized in a mixture of 50:50 miglyol: Capmul PG8, Capmul MCM, and transcutol: miglyol: Capmul PG8 is stable and does not precipitate for at least 12 days.
(実施例4)
時間経過に伴うエストラジオール溶液の物理的安定性の測定に加えて、カプセル化プロ
セス中に充填材料が安定であるかを測定することが必要である。これらの製剤を試験する
1つの方法は、充填物質への水の添加である。表5でわかるように、ポリエチレングリコ
ール400およびキャプムルMCM中6mg/gの濃度のエストラジオール溶液は少なく
とも7%の水を再結晶化なしに吸収することができるが、ミグリオール812:キャプム
ルPG8(75:25)中の同濃度の溶液は沈殿する。
Example 4
In addition to measuring the physical stability of the estradiol solution over time, it is necessary to determine whether the filler material is stable during the encapsulation process. One way to test these formulations is the addition of water to the filler material. As can be seen in Table 5, a solution of estradiol at a concentration of 6 mg / g in polyethylene glycol 400 and Capmul MCM can absorb at least 7% water without recrystallization, but Miglyol 812: Capmul PG8 (75:25 ) Solution of the same concentration in
ポリエチレングリコール400およびキャプムルMCM中12mg/gの濃度のエスト
ラジオール溶液は少なくとも7%の水を再結晶化なしに吸収することができる。すべての
キャプムルPG8含有製剤は水の添加後に濁る。しかしながら、エストラジオール再結晶
化は見られず、(いずれのエストラジオールも含まない)単独のキャプムルPG8も水の
添加後に濁ることに留意すべきである。
A solution of estradiol at a concentration of 12 mg / g in polyethylene glycol 400 and Capmul MCM can absorb at least 7% water without recrystallization. All Capmul PG8 containing formulations become cloudy after the addition of water. However, it should be noted that no estradiol recrystallisation was observed and the single Capmul PG8 (which does not contain any estradiol) is also turbid after the addition of water.
(実施例5)
例となる実施形態では、以下の充填材料を含有するカプセルが提供される。
(Example 5)
In an exemplary embodiment, a capsule containing the following filler material is provided.
(実施例6)
例となる実施形態では、以下の充填材料を含有するカプセルが提供される。
(Example 6)
In an exemplary embodiment, a capsule containing the following filler material is provided.
例となる実施形態では、以下の充填材料を含有するカプセルが提供される。 In an exemplary embodiment, a capsule containing the following filler material is provided.
上記製剤を以下のように調製する:エストラジオールをキャプムルMCMに添加し、溶
解するまで混合する。
The formulation is prepared as follows: Estradiol is added to Capmul MCM and mixed until dissolved.
(実施例7:プロゲステロン可溶性)
各種実施形態では、エストラジオールおよびプロゲステロンの両方を溶剤中に溶解する
ことができる。各種実施形態では、エストラジオールおよびプロゲステロンの両方の可溶
性は、適当なサイズの物質で治療効果的な用量を得ることができるように、好適にはサイ
ズ3〜22の楕円形または長円形カプセル中への封入に適している一般的には1mg〜1
200mgと考えられる。例えば、各種実施形態では、50mg〜100mgのプロゲス
テロンはある体積の溶剤中に溶解することができる;すなわち、可溶性はカプセル当たり
50mg〜100mgである。ミグリオールを試したところ、プロゲステロンの良好な担
体とみなすことができるが、単独では所望レベルのエストラジオールの可溶化は提供しな
かった(例えば、各種実施形態では12mg/gの可溶性が望ましくあり得る)。よって
、ミグリオールはプロゲステロンの懸濁液を含む実施形態では用いることができるが、ミ
グリオールは単体では完全可溶化プロゲステロンおよび/またはエストラジオールを有す
る実施形態において用いるには望ましくない。
(Example 7: Progesterone soluble)
In various embodiments, both estradiol and progesterone can be dissolved in a solvent. In various embodiments, the solubility of both estradiol and progesterone is preferably in oval or oval capsules of size 3-22, so that a therapeutically effective dose can be obtained with an appropriately sized substance. Suitable for encapsulation, generally 1 mg to 1
It is considered 200 mg. For example, in various embodiments, 50 mg to 100 mg of progesterone can be dissolved in a volume of solvent; that is, the solubility is 50 mg to 100 mg per capsule. Miglyol could be considered a good carrier for progesterone, but alone did not provide the desired level of estradiol solubilization (eg, 12 mg / g solubility in various embodiments may be desirable). Thus, while migliol can be used in embodiments that include a suspension of progesterone, migliol alone is not desirable for use in embodiments that have fully solubilized progesterone and / or estradiol.
表9でわかるように、キャプムルMCM中でのプロゲステロンの可溶性は〜73mg/
gである。従って、400mgの溶剤中に200mgのプロゲステロンを懸濁させると、
用量の一部(〜14%)はすでに溶解しているが、残りはまだ懸濁液である。いくつかの
態様および実施形態では、再結晶化の可能性を最小化するため、製剤中のプロゲステロン
の部分可溶性を最小化することが望ましい。
As can be seen in Table 9, the solubility of progesterone in Capmul MCM is ~ 73 mg /
g. Thus, when 200 mg progesterone is suspended in 400 mg solvent,
Part of the dose (~ 14%) is already dissolved, but the rest is still a suspension. In some aspects and embodiments, it is desirable to minimize the partial solubility of progesterone in the formulation to minimize the possibility of recrystallization.
73mg/gの可溶性に基づき、50mgの可溶化プロゲステロンのカプセルを製造す
るのに必要なカプセルサイズは685mgである。従って、50mgのプロゲステロンお
よび2mgのエストラジオールの可溶化製剤を製造することは実行可能であると示された
。ミグリオールはもっとも低い可溶性を有したが、その溶剤はエストラジオールを溶解す
ることができず、従ってさらなる実験は2番目に低いキャプムルMCMで進めることを決
定した。2mgのエストラジオールは685mgのキャプムルMCM中に溶解することも
できることも見出した。
Based on a solubility of 73 mg / g, the capsule size required to produce a 50 mg solubilized progesterone capsule is 685 mg. Therefore, it has been shown that it is feasible to produce a solubilized formulation of 50 mg progesterone and 2 mg estradiol. Miglyol had the lowest solubility, but its solvent was unable to dissolve estradiol, so further experiments decided to proceed with the second lowest Capmul MCM. It was also found that 2 mg estradiol could be dissolved in 685 mg Capmul MCM.
加えて、9:1の比で組み合わされたゲルシール44/14およびキャプムルMCMの
溶剤中のプロゲステロンの可溶性は約86mg/gまで増加することを見出した。従って
、各種実施形態では、プロゲステロンおよび/またはエストラジオールをキャプムルMC
Mおよびゲルシール44/14の、キャプムルMCMのゲルシール44/14に対する比
が9:1である、システム中に溶解することができる。
In addition, it was found that the solubility of progesterone in the gel seal 44/14 and Capmul MCM solvent combined in a 9: 1 ratio increased to about 86 mg / g. Accordingly, in various embodiments, progesterone and / or estradiol are added to Capmul MC.
M and gel seal 44/14 can be dissolved in the system with a 9: 1 ratio of Capmul MCM to gel seal 44/14.
(実施例7)
例となる実施形態では、以下の完全可溶化プロゲステロンおよびエストラジオールを有
する充填材料を含有するカプセルが提供される。
(Example 7)
In an exemplary embodiment, a capsule is provided containing a filler material having the following fully solubilized progesterone and estradiol.
表11に示したようなカプセルはいずれかの適切な方法で製造することができる。この
実施例の目的のため、混合は羽根車、撹拌器、または他の適切な手段により促進すること
ができる。またこの実施例の目的のため、加熱および/または混合は、窒素ガスN2のよ
うな、不活性または比較的不活性なガス雰囲気下で行うことができる。この実施例の目的
のための混合および/または加熱は、ステンレススチール容器のような、いずれかの適切
な容器内で行うことができる。
Capsules such as those shown in Table 11 can be manufactured by any suitable method. For purposes of this example, mixing can be facilitated by an impeller, stirrer, or other suitable means. Also for purposes of this example, the heating and / or mixing, such as nitrogen gas N 2, can be carried out in an inert or relatively inert gas atmosphere. Mixing and / or heating for the purposes of this example can be done in any suitable container, such as a stainless steel container.
例えば、キャプムルMCMは30℃〜50℃、より好適には35℃〜45℃、より好適
には40℃+/−2℃まで加熱することができる。ゲルシール44/14をキャプムルM
CMに添加し、溶解するまで混合することができる。添加はすべて一度で行ってもよく、
または時間をかけて徐々に行ってもよい。熱はゲルシール44/14およびキャプムルM
CMの混合中に継続して加えることができる。
For example, Capmul MCM can be heated to 30 ° C. to 50 ° C., more preferably 35 ° C. to 45 ° C., more preferably 40 ° C. + / − 2 ° C. Capsule M with gel seal 44/14
It can be added to the CM and mixed until dissolved. All additions can be done at once,
Or you may carry out gradually over time. Heat is gel seal 44/14 and Capmul M
It can be added continuously during the mixing of the CM.
熱はゲルシール44/14およびキャプムルMCM混合物から除去することができる。
エストラジオール半水和物を混合物に添加することができる。添加はすべて一度で行って
もよく、または時間をかけて徐々に行ってもよい。微粒子化プロゲステロンを次にゲルシ
ール44/14、キャプムルMCMおよびエストラジオール半水和物の混合物に添加し、
溶解するまで混合することができる。添加はすべて一度で行ってもよく、または時間をか
けて徐々に行ってもよい。
Heat can be removed from the gel seal 44/14 and the Capmul MCM mixture.
Estradiol hemihydrate can be added to the mixture. All additions may be made at once, or may be done gradually over time. Micronized progesterone is then added to the mixture of gel seal 44/14, capmul MCM and estradiol hemihydrate,
Mix until dissolved. All additions may be made at once, or may be done gradually over time.
(実施例8)
例となる実施形態では、以下の懸濁化プロゲステロンを有する充填材料を含有するカプ
セルが提供される。
(Example 8)
In an exemplary embodiment, a capsule containing a filling material having the following suspended progesterone is provided.
上記製剤を以下のように調製する:ミグリオールを約45℃まで加熱する。ゲルシール
44/14を添加し、溶解するまで混合する。BHTを添加し、溶解するまで混合する。
プロゲステロンを懸濁させ、コロイドミルに通す。得られた充填物質はカプセル化に用い
ることができる。
The formulation is prepared as follows: Miglyol is heated to about 45 ° C. Add gel seal 44/14 and mix until dissolved. Add BHT and mix until dissolved.
Suspend progesterone and pass through a colloid mill. The resulting filling material can be used for encapsulation.
例となる実施形態では、以下の部分可溶化プロゲステロンを有する充填材料を含有する
カプセルが提供される。
In an exemplary embodiment, a capsule containing a filler material having the following partially solubilized progesterone is provided.
プロゲステロンおよび部分可溶化プロゲステロンの懸濁液について、ゲルシール44/
14を1%〜2%w/wで添加し、粘度を増加させることができる。上記製剤を以下のよ
うに調製する:キャプムルMCMを約65℃まで加熱する。ゲルシール44/14を添加
し、溶解するまで混合する。熱を除去する。プロゲステロンを添加し、混合物をコロイド
ミルに通す。得られた充填物質はカプセル化に用いることができる。
For suspensions of progesterone and partially solubilized progesterone, gel seal 44 /
14 can be added at 1% to 2% w / w to increase the viscosity. The formulation is prepared as follows: Capmul MCM is heated to about 65 ° C. Add gel seal 44/14 and mix until dissolved. Remove heat. Progesterone is added and the mixture is passed through a colloid mill. The resulting filling material can be used for encapsulation.
(実施例9)
例となる実施形態では、以下の懸濁化プロゲステロンを有する充填材料を含有するカプ
セルが提供される。
Example 9
In an exemplary embodiment, a capsule containing a filling material having the following suspended progesterone is provided.
各種実施形態では、ミグリオールは約35〜95重量%;ゲルシール44/14は約0
.5〜30重量%;およびBHTは約0.01〜0.1重量%の範囲内の量で存在し得る
。
In various embodiments, miglyol is about 35-95% by weight; gel seal 44/14 is about 0.
. 5-30% by weight; and BHT may be present in an amount in the range of about 0.01-0.1% by weight.
(実施例10)
この実施例の目的のため、粒径分析はベックマン装置を用いることにより行う。各種実
施形態による微粒子化プロゲステロンを含むAPI試料を分析用に提供する。
(Example 10)
For purposes of this example, particle size analysis is performed by using a Beckman device. An API sample comprising micronized progesterone according to various embodiments is provided for analysis.
約0.01gの各種実施形態によるAPI試料をコールター1Bおよび10mLの脱イ
オン水と組み合わせた。超音波処理を15秒間行った。ULMを備えたベックマン装置で
90秒間分析を行った。ベックマン装置はフラウンホーファー光学モデルを用いるように
構成した。ベックマン装置は、試料が4.279μmのX50、7.442μmのX75
、および1.590μmのX25を有することを示した。ベックマン装置は、平均粒径が
4.975μmであり、中間粒径が4.279μmであり、モード粒径が6.453μm
であり、標準偏差が3.956μmであることも示した。得られた粒子分布のグラフを図
4に示す。
Approximately 0.01 g of API sample according to various embodiments was combined with Coulter 1B and 10 mL of deionized water. Sonication was performed for 15 seconds. Analysis was performed for 90 seconds on a Beckman apparatus equipped with a ULM. The Beckmann device was configured to use the Fraunhofer optical model. The Beckman device has a sample of X279 with a 4.279 μm and X75 with a 7.442 μm
And having an X25 of 1.590 μm. The Beckmann apparatus has an average particle size of 4.975 μm, an intermediate particle size of 4.279 μm, and a mode particle size of 6.453 μm.
It was also shown that the standard deviation was 3.956 μm. The resulting particle distribution graph is shown in FIG.
(実施例11)
約200mgの微粒子化プロゲステロンおよび2mgのエストラジオールを有する製剤
試料を油で分散させた。MLMを備えるベックマン装置で60秒間分析を行った。ベック
マン装置はフラウンホーファー光学モデルを用いるように構成した。ベックマン装置は、
試料が11.0μmのX50、17.3μmのX75、および5.3μmのX25を有す
ることを示した。ベックマン装置は、平均粒径が11.8μmであり、中間粒径が11.
04μmであり、モード粒径が13.6μmであり、標準偏差が7.8μmであることも
示した。
(Example 11)
Formulation samples having about 200 mg micronized progesterone and 2 mg estradiol were dispersed with oil. The analysis was performed for 60 seconds on a Beckman device equipped with an MLM. The Beckmann device was configured to use the Fraunhofer optical model. Beckman device
The sample was shown to have 11.0 μm X50, 17.3 μm X75, and 5.3 μm X25. The Beckmann apparatus has an average particle size of 11.8 μm and an intermediate particle size of 11.
It was also shown to be 04 μm, the mode particle size was 13.6 μm, and the standard deviation was 7.8 μm.
(実施例12)
最終溶液中でのプロゲステロンの可溶性を増加させるため、ゲルシール44/14を約
10%w/wで添加した。
定量配合:バッチサイズ10,000カプセル
(Example 12)
Gel seal 44/14 was added at about 10% w / w to increase the solubility of progesterone in the final solution.
Fixed amount formulation: 10,000 capsules in batch size
最終製剤の例を表15に提供する。製造プロセスは以下のとおりである。キャプムルM
CMを40℃まで加熱する。ゲルシール44/14を添加し、溶解するまで混合する。熱
を除去する。エストラジオールを添加し、溶解するまで混合する。微粒子化プロゲステロ
ンを次に添加し、溶解するまで混合する。
Examples of final formulations are provided in Table 15. The manufacturing process is as follows. Capmul M
Heat the CM to 40 ° C. Add gel seal 44/14 and mix until dissolved. Remove heat. Add estradiol and mix until dissolved. Micronized progesterone is then added and mixed until dissolved.
(実施例13)
例となる実施形態では、以下の完全可溶化エストラジオールおよび部分可溶化プロゲス
テロンを有する充填材料を含有するカプセルが提供される。
(Example 13)
In an exemplary embodiment, a capsule is provided containing a filler material having the following fully solubilized estradiol and partially solubilized progesterone.
製造プロセスは以下のとおりである。キャプムルMCMを65℃まで加熱する。ゲルシ
ール44/14を添加し、溶解するまで混合する。熱を除去する。エストラジオールを添
加し、溶解するまで混合する。微粒子化プロゲステロンを次に添加し、分散させる。混合
物を次にコロイドミルに通す。得られた充填物質はカプセル化に用いることができる。
The manufacturing process is as follows. Heat Capmul MCM to 65 ° C. Add gel seal 44/14 and mix until dissolved. Remove heat. Add estradiol and mix until dissolved. Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resulting filling material can be used for encapsulation.
(実施例14)
例となる実施形態では、以下の完全可溶化エストラジオールおよび部分可溶化プロゲス
テロンを有する充填材料を含有するカプセルが提供される。
(Example 14)
In an exemplary embodiment, a capsule is provided containing a filler material having the following fully solubilized estradiol and partially solubilized progesterone.
製造プロセスは以下のとおりである。キャプムルMCMを65℃まで加熱する。ゲルシ
ール44/14を添加し、溶解するまで混合する。熱を除去する。エストラジオールを添
加し、溶解するまで混合する。微粒子化プロゲステロンを次に添加し、分散させる。混合
物を次にコロイドミルに通す。得られた充填物質はカプセル化に用いることができる。
The manufacturing process is as follows. Heat Capmul MCM to 65 ° C. Add gel seal 44/14 and mix until dissolved. Remove heat. Add estradiol and mix until dissolved. Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resulting filling material can be used for encapsulation.
(実施例15:摂食条件下でのプロゲステロンおよびエストラジオールの複合物の実験)
この以下の実験プロトコルを用い、24人の正常で健康な成人の閉経後期の女性被験者
に摂食条件下で投与した、実施例14に記載されるプロセスによって調製されたプロゲス
テロン(200mg)およびエストラジオール(2.0mg)を含む本開示の複合製品に
ついて生物学的利用能および生物学的同等性のパラメータを構築し、200mgのプロメ
トリウム(PROMETRIUM;登録商標)(Catalent Pharmaceu
ticals、フロリダ州セントピーターズバーグ)および2.0mgのエストレース(
ESTRACE;登録商標)(Bristol−Myers Squibb Co.、ニ
ュージャージー州プリンストン)と比較した。
Example 15: Experiment of a composite of progesterone and estradiol under feeding conditions
Using this following experimental protocol, progesterone (200 mg) and estradiol (200 mg) prepared by the process described in Example 14 were administered to 24 normal healthy adult postmenopausal female subjects under fed conditions. Bioavailability and bioequivalence parameters were constructed for the composite product of the present disclosure containing 2.0 mg) and 200 mg of PROMETURIUM® (Catalyst Pharmaceu)
ticals, St. Petersburg, FL) and 2.0 mg estrace (
ESSTRACE® (Bristol-Myers Squibb Co., Princeton, NJ).
実験デザイン:オープンラベル、バランス、ランダム、2処理、2期間、2連続、単回
服薬、2方向クロスオーバーである。
Experimental design: open label, balance, random, 2 treatments, 2 periods, 2 consecutive, single dose, 2 way crossover.
被験者は、各期間、服薬前少なくとも11.00時間〜服薬後少なくとも48.00時
間臨床施設に収容され、次の服薬日まで少なくとも14日をウォッシュアウト期間とした
。
The subjects were housed in clinical facilities at least 11.00 hours before taking to at least 48.00 hours after taking each period, and the washout period was at least 14 days until the next taking day.
被験者は少なくとも約10.00時間断食した後、高脂肪、高カロリーの朝食を取り、
その後服薬し、服薬後さらに04.00時間断食した。
Subjects fasted for at least about 10.00 hours, then had a high fat, high calorie breakfast,
The patient then took the medicine and fasted for an additional 04.00 hours after taking the medicine.
標準的な食事が服薬後それぞれ約04.00、09.00、13.00、25.00、
29.00、34.00および38.00時間に提供された。
Standard meals are about 04.00, 09.00, 13.00, 23.00,
Provided at 29.00, 34.00 and 38.00 hours.
水は(服薬中に与えられる水以外)服薬前少なくとも約01時間〜服薬後約01時間制
限された。その他の時間、飲み水は自由に提供された。
Water was restricted from at least about 01 hours before taking to about 01 hours after taking (other than water given during taking). During other times, drinking water was provided freely.
被験者はカフェインおよび/またはキサンチン含有製品(すなわち、コーヒー、お茶、
チョコレート、およびカフェイン含有ソーダ、コーラ、等)の摂取を服薬前少なくとも約
24.00時間および実験中、グレープフルーツおよび/またはそのジュースならびにポ
ピー含有食品の摂取を服薬前少なくとも約48.00時間および実験中は控えるよう指導
された。
Subjects are caffeine and / or xanthine-containing products (ie coffee, tea,
Chocolate, and caffeine-containing soda, cola, etc.) at least about 24.00 hours prior to taking the experiment and experiment, and at least about 48.00 hours before taking the intake of grapefruit and / or its juice and poppy containing food. He was instructed to refrain from inside.
被験者は服薬後最初の約4.00時間はまっすぐ座ったままとし、この期間は必要な動
作のみ許可された。その後被験者は実験の残りの期間は自由に動き回ることを許可された
。被験者は制限期間中(有害事象後に医師の指示があった場合を除き)横になることを許
可されなかった。
Subjects remained sitting straight for the first approximately 4.00 hours after taking medication, and only necessary movements were allowed during this period. Subjects were then allowed to move around freely for the remainder of the experiment. Subjects were not allowed to lie down during the restricted period (unless they were instructed by a physician after an adverse event).
被験者は実験開始前14日以内および実験中はいずれの処方薬も服用しないよう指導さ
れた。被験者は実験開始前7日以内および実験中はいずれの市販の医薬製品、ハーブ薬、
等も服用しないよう指導された。
Subjects were instructed not to take any prescription drugs within 14 days prior to the start of the experiment and during the experiment. Subjects should be able to use any of the commercially available pharmaceutical products, herbal drugs,
Etc. were instructed not to take them.
少なくとも約10.00時間の一晩の断食後、高脂肪高カロリーの朝食が実験製品の投
与の約30分前に出された。すべての被験者は出されてから約30分以内に朝食を全部食
べる必要があり、(ランダムスケジュールにより)プロゲステロン200mgおよびエス
トラジオール2mgのタブレットの試験製品(T)またはプロメトリウム(登録商標)(
プロゲステロン)ソフトゲルカプセル200mgおよびエストレース(登録商標)(エス
トラジオール)タブレット2mgの対照製品(R)の単回用量が摂食条件下、各期間周囲
温度で、座った姿勢で、約240mLの水で投与された。服薬コンプライアンスを評価す
るため十分なマウスチェックが行われた。
After an overnight fast of at least about 10.00 hours, a high fat, high calorie breakfast was served about 30 minutes before administration of the experimental product. All subjects must eat the entire breakfast within about 30 minutes of serving, and (by random schedule) 200 mg of progesterone and 2 mg of estradiol tablet test product (T) or Promethorium® (
A single dose of Progesterone) Softgel Capsule 200 mg and Estrace® (Estradiol) Tablet 2 mg Control Product (R) was fed with approximately 240 mL of water in the sitting position at ambient temperature for each period under fed conditions Was administered. Sufficient mouse checks were performed to assess medication compliance.
すべての被験者は実験の最後にまたは必要に応じて臨床検査について評価された。 All subjects were evaluated for clinical testing at the end of the experiment or as needed.
各期間、23の血液試料が回収された。服薬前血液試料(10mL)は−01.00、
−00.50、00.00時間、服薬後血液試料(各0.8mL)は00.25、00.
50、00.67、00.83、01.00、01.33、01.67、02.00、0
2.50、03.00、04.00、05.00、06.00、07.00、08.00
、10.00、12.00、18.00、24.00および48.00時間で、被験者の
前腕の静脈の1つに設置された留置カニューレによってラベルをつけたK2EDTAバキ
ュテナーに回収された。各静脈内留置カニューレはできる限りその場に保持され、通常の
生理食塩水溶液中10IU/mLのヘパリン約0.5mLを注入することにより、服薬後
試料の回収のために維持された。こうした場合、血液試料はヘパリン含有血液の最初の0
.5mLを排出した後回収された。各カニューレは24.00時間試料が回収された後も
しくはそれより早く、または詰まった場合除去された。
During each period, 23 blood samples were collected. The pre-medication blood sample (10 mL) is -01.00,
-0.050, 00.00 hours, post-medication blood samples (0.8 mL each) 00.25, 00.
50, 0.067, 0.83, 01.00, 01.33, 01.67, 02.00, 0
2.50, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00
At 10.00, 12.00, 18.00, 24.00 and 48.00 hours, they were collected in a K2EDTA vacutainer labeled by an indwelling cannula placed in one of the subject's forearm veins. Each intravenous indwelling cannula was kept in place as much as possible and maintained for post-dose sample collection by injecting approximately 0.5 mL of 10 IU / mL heparin in normal saline solution. In such cases, the blood sample is the first 0 of heparin-containing blood.
. It was recovered after draining 5 mL. Each cannula was removed after 24.00 hours of sample collection or earlier or when clogged.
実験の最後に、試料は、試料の完全性を維持するため十分なドライアイスを含有するボ
ックスに入れてバイオ分析施設へ移された。これらの試料は分析までバイオ分析施設に−
70℃±20℃の温度で保存された。
At the end of the experiment, the samples were transferred to a bioanalysis facility in a box containing enough dry ice to maintain sample integrity. These samples are stored in bioanalysis facilities until analysis
Stored at a temperature of 70 ° C. ± 20 ° C.
血漿試料中のプロゲステロン(補正および未補正)、エストラジオール(非抱合)およ
びエストロン(合計)を、有効なLC−MS/MS法を用いてアッセイする。
Progesterone (corrected and uncorrected), estradiol (unconjugated) and estrone (total) in plasma samples are assayed using a validated LC-MS / MS method.
このプロトコルを用いる断食実験も行われた。しかしながら、試験および対照薬剤の投
与前の高脂肪の食事ではなく、各被験者は用量投与前少なくとも12時間断食した。
Fasting experiments using this protocol were also performed. However, each subject fasted for at least 12 hours prior to dose administration, rather than a high fat diet prior to administration of the test and control drugs.
(実施例16)
各種実施形態による製造方法を図1〜3に示す。図1を参照すると、充填材料の製造方
法100が示される。ステップ102は油性担体を40℃±5℃まで加熱することを含む
。加熱はいずれかの適切な手段によって達成することができる。加熱は、ステンレススチ
ール容器のような、いずれかの適切な容器で行うことができる。油性担体は、本明細書に
記載されるいずれかの油性担体、例えば、キャプムルMCMであってもよい。
(Example 16)
Manufacturing methods according to various embodiments are shown in FIGS. Referring to FIG. 1, a filling material manufacturing method 100 is shown. Step 102 includes heating the oily carrier to 40 ° C. ± 5 ° C. Heating can be accomplished by any suitable means. Heating can be done in any suitable container, such as a stainless steel container. The oily carrier may be any oily carrier described herein, such as Capmul MCM.
ステップ104はゲルシール44/14を油性担体と混合することを含む。混合は羽根
車、撹拌器、または他の適切な手段により促進することができる。ステップ102は、窒
素ガスN2のような、不活性または比較的不活性なガス雰囲気下で行うことができる。混
合は、ステンレススチール容器のような、いずれかの適切な容器で行うことができる。
Step 104 includes mixing the gel seal 44/14 with an oily carrier. Mixing can be facilitated by an impeller, stirrer, or other suitable means. Step 102 can be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Mixing can be done in any suitable container, such as a stainless steel container.
ステップ106は、エストラジオールを油性担体およびゲルシール44/14の混合物
中に混合することを含む。混合はスチールタンクまたはバットにおいて行うことができる
。混合は羽根車、撹拌器、または他の適切な手段により促進することができる。ステップ
106は、窒素ガスN2のような、不活性または比較的不活性なガス雰囲気下で行うこと
ができる。
Step 106 includes mixing estradiol into a mixture of oily carrier and gel seal 44/14. Mixing can take place in a steel tank or bat. Mixing can be facilitated by an impeller, stirrer, or other suitable means. Step 106 can be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 .
ステップ108は、室温まで冷却することを含む。冷却は操作なしで行うことができ、
または冷却は冷却システムの適用により補助することができる。
Step 108 includes cooling to room temperature. Cooling can be done without operation,
Or cooling can be assisted by application of a cooling system.
ステップ110は、微粒子化プロゲステロンを油性担体、エストラジオールおよびゲル
シール44/14の混合物中に混合することを含む。混合はスチールタンクまたはバット
において行うことができる。混合は羽根車、撹拌器、または他の適切な手段により促進す
ることができる。ステップ110は、窒素ガスN2のような、不活性または比較的不活性
なガス雰囲気下で行うことができる。ステップ112は脱ガス化を含む。ステップ112
から得られる混合物は、ソフトゲルカプセルへの製造に適した充填材料を含む。
Step 110 includes mixing micronized progesterone into a mixture of oily carrier, estradiol and gel seal 44/14. Mixing can take place in a steel tank or bat. Mixing can be facilitated by an impeller, stirrer, or other suitable means. Step 110, such as nitrogen gas N 2, it can be carried out in an inert or relatively inert gas atmosphere. Step 112 includes degassing. Step 112
The mixture obtained from comprises a filling material suitable for production into soft gel capsules.
図2を参照すると、ソフトゲルカプセル、すなわち、ゲル物質製造200が示される。
ステップ202は、グリセリンを水と混合することを含む。ステップ202において用い
られる水は、逆浸透、オゾン化、(例えば、炭素カラムを通す)濾過、等のような、いず
れかの適切な手段により精製することができる。混合は羽根車、撹拌器、または他の適切
な手段により促進することができる。ステップ202は、窒素ガスN2のような、不活性
または比較的不活性なガス雰囲気下で行うことができる。加熱は温度が80℃±5℃に達
するまで行うことができる。
Referring to FIG. 2, a soft gel capsule or gel material manufacture 200 is shown.
Step 202 includes mixing glycerin with water. The water used in step 202 can be purified by any suitable means such as reverse osmosis, ozonation, filtration (eg, through a carbon column), and the like. Mixing can be facilitated by an impeller, stirrer, or other suitable means. Step 202 can be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Heating can be performed until the temperature reaches 80 ° C. ± 5 ° C.
ステップ204は、グリセリン水混合物へのゼラチンの添加を含む。混合は羽根車、撹
拌器、または他の適切な手段により促進することができる。ステップ204は、窒素ガス
N2のような、不活性または比較的不活性なガス雰囲気下で行うことができる。ステップ
204では真空を引き、脱気することができる。
Step 204 includes the addition of gelatin to the glycerin water mixture. Mixing can be facilitated by an impeller, stirrer, or other suitable means. Step 204 can be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . In step 204, a vacuum can be pulled and degassed.
ステップ206は染料のような着色剤の添加を含む。着色剤としては、商標OPATI
NTで販売される製品または他の適切な着色剤を挙げることができる。ステップ206は
、窒素ガスN2のような、不活性または比較的不活性なガス雰囲気下で行うことができる
。ステップ208は脱ガス化を含む。ステップ208から得られる混合物は、ソフトゲル
カプセルの製造においてゲルカプセルとして用いるのに適したゲルカプセル材料を含むこ
とができる。
Step 206 includes the addition of a colorant such as a dye. Colorants include the trademark OPATI
Mention may be made of products sold at NT or other suitable colorants. Step 206 can be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Step 208 includes degassing. The mixture resulting from step 208 can include a gel capsule material suitable for use as a gel capsule in the manufacture of a soft gel capsule.
図3を参照すると、ソフトゲルカプセル組み立てプロセス300が示される。ステップ
302は充填材料を加熱することを含む。充填材料はいずれかの適切な温度まで加熱する
ことができる。各種実施形態では、充填材料を30℃±3℃まで加熱する。充填材料は充
填ホッパーにおいて加熱することができる。充填ホッパーはある体積の充填材料を保持、
および/または充填材料を制御体積で分注するように構成された装置を備えることができ
る。
Referring to FIG. 3, a soft gel capsule assembly process 300 is shown. Step 302 includes heating the fill material. The filler material can be heated to any suitable temperature. In various embodiments, the filler material is heated to 30 ° C. ± 3 ° C. The filling material can be heated in a filling hopper. A filling hopper holds a volume of filling material,
And / or a device configured to dispense the filler material in a controlled volume.
ステップ304はゲル物質を充填することを含む。ゲル物質は図2のステップ208に
おいて製造されたゲルカプセル材料から得ることができる。充填は、充填材料をゲルカプ
セル材料により画定される体積内に注入、配置、またはそうでなければ堆積することによ
り行うことができる。充填はエンキャプスレータにおいて行うことができる。スプレッダ
ーボックスは55℃±10℃の温度であり得る。ウェッジ温度は38℃±3℃であり得る
。ドラム冷却温度は4℃±2℃であり得る。エンキャプスレータはミグリオール812ま
たは他の適切な潤滑剤を用いて潤滑化することができる。ステップ304はこうして1つ
以上のソフトゲルカプセルを製造する。充填はスプレッダーボックスノブを用いる厚さ0
.85mm±0.05mmのリボンの製造を含む。充填材料をゲルに注入し、標的重量±
5%(すなわち、650±33mgおよび325±16.3mg)を有する充填重量をも
たらすことができる。
Step 304 includes filling the gel material. The gel material can be obtained from the gel encapsulant material produced in step 208 of FIG. Filling can be done by pouring, placing, or otherwise depositing the filling material within the volume defined by the gel capsule material. Filling can be done in an encapsulator. The spreader box can be at a temperature of 55 ° C. ± 10 ° C. The wedge temperature can be 38 ° C. ± 3 ° C. The drum cooling temperature can be 4 ° C. ± 2 ° C. The encapsulator can be lubricated with Miglyol 812 or other suitable lubricant. Step 304 thus produces one or more soft gel capsules. Filling is 0 thickness using spreader box knob
. Includes the production of 85 mm ± 0.05 mm ribbons. Fill material into gel and target weight ±
A fill weight with 5% (ie 650 ± 33 mg and 325 ± 16.3 mg) can be provided.
ステップ306はソフトゲルカプセルの乾燥を含む。乾燥はタンブルドライヤー、トレ
イドライヤー、またはこれらの組み合わせで行うことができる。例えば、乾燥は約10分
〜約120分間タンブルドライバスケットで行うことができる。乾燥は乾燥室で約24時
間〜約72時間継続することができる。ステップ308は検査および/または研磨を含む
ことができる。研磨はイソプロピルアルコールで行うことができる。ステップ310は包
装を含むことができる。包装はいずれかの適切な手段によって達成することができる。包
装は、ソフトゲルカプセルをブリスターパック、ボトル、ボックス、パウチ、または他の
許容可能なパッケージに包装することを含む。
Step 306 includes drying the soft gel capsule. Drying can be performed with a tumble dryer, a tray dryer, or a combination thereof. For example, drying can be performed in a tumble dry basket for about 10 minutes to about 120 minutes. Drying can continue in the drying room for about 24 hours to about 72 hours. Step 308 can include inspection and / or polishing. Polishing can be performed with isopropyl alcohol. Step 310 can include packaging. Packaging can be achieved by any suitable means. Packaging includes packaging soft gel capsules in blister packs, bottles, boxes, pouches, or other acceptable packages.
Claims (52)
剤。 A pharmaceutical formulation comprising at least one of solubilized estradiol and micronized progesterone.
医薬製剤。 2. The pharmaceutical formulation of claim 1, wherein the progesterone has an X50 particle size value range of less than about 15 μM.
に記載の医薬製剤。 The micronized progesterone has an X90 particle size value range of less than about 25 μM.
A pharmaceutical preparation according to 1.
ゲステロンの少なくとも1つを含む医薬製剤。 A pharmaceutical formulation comprising at least one of solubilized estradiol and micronized progesterone in combination with partially solubilized progesterone.
製剤。 6. The pharmaceutical formulation of claim 5, wherein the progesterone has an X50 particle size value of less than about 15 μM.
に記載の医薬製剤。 6. The micronized progesterone has an X90 particle size value range of less than about 25 μM.
A pharmaceutical preparation according to 1.
。 A pharmaceutical formulation comprising at least one of solubilized estradiol and solubilized progesterone.
量および同等の時間で同一のUSP溶解装置を用いて試験した場合、プロメトリウム(登
録商標)により提供される溶解と比較してより均一なプロゲステロン溶解を提供する、医
薬製剤。 10. A pharmaceutical formulation according to any one of claims 1, 5 and 9, when tested using the same USP dissolution apparatus with an equivalent active ingredient content and an equivalent time. A pharmaceutical formulation that provides more uniform progesterone dissolution compared to the dissolution provided by.
すると、同等の有効性成分量のプロメトリウムを投与して投与後に同等のサンプリング時
間で測定するときの患者内の血中濃度のばらつきに比べて、患者内の血中濃度のばらつき
が低減される、医薬製剤。 2. The pharmaceutical preparation according to claim 1, wherein when the preparation containing progesterone is administered to a subject, the amount of promethorium having an equivalent active ingredient amount is administered, and measurement is performed at the same sampling time after administration. A pharmaceutical preparation in which the variation in blood concentration within a patient is reduced compared to the variation in blood concentration of.
すると、同等の有効性成分量のプロメトリウムを投与して投与後に同等のサンプリング時
間で測定するときの患者間の血中濃度のばらつきに比べて、患者間の血中濃度のばらつき
が低減される、医薬製剤。 2. The pharmaceutical preparation according to claim 1, wherein when the preparation containing progesterone is administered to a subject, an equivalent amount of promethorium is administered and the measurement is performed at the same sampling time after administration. A pharmaceutical preparation in which the variation in blood concentration among patients is reduced compared to the variation in blood concentration.
すると、同等の有効性成分量のプロメトリウムを投与して投与後に同等のサンプリング時
間で測定するときの患者内の血中濃度のばらつきに比べて、患者内の血中濃度のばらつき
が低減される、医薬製剤。 6. The pharmaceutical preparation according to claim 5, wherein when the preparation containing progesterone is administered to a subject, the amount of promethorium having an equivalent active ingredient amount is administered, and measurement is performed at the same sampling time after administration. A pharmaceutical preparation in which the variation in blood concentration within a patient is reduced compared to the variation in blood concentration of.
すると、同等の有効性成分量のプロメトリウムを投与して投与後に同等のサンプリング時
間で測定するときの患者間の血中濃度のばらつきに比べて、患者間の血中濃度のばらつき
が低減される、医薬製剤。 6. The pharmaceutical preparation according to claim 5, wherein when the preparation containing progesterone is administered to a subject, an equivalent amount of promethorium is administered and the measurement is performed at the same sampling time after administration. A pharmaceutical preparation in which the variation in blood concentration among patients is reduced compared to the variation in blood concentration.
すると、同等の有効性成分量のプロメトリウムを投与して投与後に同等のサンプリング時
間で測定するときの患者内の血中濃度のばらつきに比べて、患者内の血中濃度のばらつき
が低減される、医薬製剤。 10. The pharmaceutical preparation according to claim 9, wherein when the preparation containing progesterone is administered to a subject, the same effective ingredient amount of promethorium is administered, and measurement is performed at the same sampling time after administration. A pharmaceutical preparation in which the variation in blood concentration within a patient is reduced compared to the variation in blood concentration of.
すると、同等の有効性成分量のプロメトリウムを投与して投与後に同等のサンプリング時
間で測定するときの患者間の血中濃度のばらつきに比べて、患者間の血中濃度のばらつき
が低減される、医薬製剤。 10. The pharmaceutical preparation according to claim 9, wherein when the preparation containing progesterone is administered to a subject, the amount of promethlium having an equivalent active ingredient amount is administered, and measurement is performed with an equivalent sampling time after administration. A pharmaceutical preparation in which the variation in blood concentration among patients is reduced compared to the variation in blood concentration.
、請求項18に記載の医薬製剤。 The pharmaceutical formulation according to claim 18, wherein the oral dosage form is selected from the group consisting of hard capsules and soft capsules.
、請求項20に記載の医薬製剤。 21. The pharmaceutical formulation according to claim 20, wherein the oral dosage form is selected from the group consisting of hard capsules and soft capsules.
、請求項22に記載の医薬製剤。 The pharmaceutical formulation according to claim 22, wherein the oral dosage form is selected from the group consisting of hard capsules and soft capsules.
製剤であって、前記油がピーナッツ油ではない、医薬製剤。 10. A pharmaceutical formulation according to any one of claims 1, 5 and 9, further comprising at least one oil, wherein the oil is not peanut oil.
らの誘導体、またはこれらの組み合わせからなる群から選択される中鎖長を有する、請求
項23に記載の医薬製剤。 24. The pharmaceutical formulation of claim 23, wherein the at least one oil has a medium chain length selected from the group consisting of at least one mono, di, and triglyceride, derivatives thereof, or combinations thereof.
酸;リノール酸;コハク酸;グリセリン;モノ、ジ、またはトリグリセリド、これらの組
み合わせおよび誘導体;ポリエチレングリコール;ポリエチレングリコールグリセリド(
ゲルシール);プロピレングリコール;カプリル酸/カプリン酸トリグリセリド(ミグリ
オール);カプロン酸/カプリル酸/カプリン酸/ラウリル酸トリグリセリド;カプリル
酸/カプリン酸/リノール酸トリグリセリド;カプリル酸/カプリン酸/コハク酸トリグ
リセリド;プロピレングリコールモノカプリレート;プロピレングリコールモノカプラー
ト(キャプムルPG−8および10);プロピレングリコールジカプリレート;プロピレ
ングリコールジカプリレート;中鎖モノおよびジグリセリド(キャプムルMCM);ジエ
チレングリコールモノエステル(トランスクトール);ジエチレングリコールモノエチル
;飽和ココナッツおよびパーム核油のエステルおよびこれらの誘導体;分留植物脂肪酸の
トリグリセリド、及びこれらの組み合わせおよび誘導体の少なくとも1つからなる群から
選択される、請求項23のいずれか1項に記載の医薬製剤。 Capron fatty acid; caprylic fatty acid; capric fatty acid; tauric acid; myristic acid; linoleic acid; succinic acid; glycerine;
Propylene glycol; caprylic acid / capric acid triglyceride (miglyol); caproic acid / caprylic acid / capric acid / lauric acid triglyceride; caprylic acid / capric acid / linoleic acid triglyceride; caprylic acid / capric acid / succinic acid triglyceride; propylene Propylene glycol monocaprate (Capmul PG-8 and 10); Propylene glycol dicaprylate; Propylene glycol dicaprylate; Medium chain mono and diglycerides (Capmul MCM); Diethylene glycol monoester (Transcutol); Diethylene glycol Monoethyl; esters of saturated coconut and palm kernel oils and their derivatives; triglycerides of fractionated plant fatty acids, and these It is selected from the combination, and at least one from the group consisting of derivatives, pharmaceutical formulation according to any one of claims 23.
に記載の医薬製剤。 26. The saturated coconut and palm kernel oil derivatives are these esters.
A pharmaceutical preparation according to 1.
リオール829からなる群から選択される、請求項25に記載の医薬製剤。 26. The pharmaceutical formulation of claim 25, wherein the oil is selected from the group consisting of Miglyol 810, Miglyol 812, Miglyol 818 and Miglyol 829.
に記載の医薬製剤。 26. The polyethylene glycol glyceride is gel seal 44/14.
A pharmaceutical preparation according to 1.
酸/カプリン酸トリグリセリドを含む、請求項25に記載の医薬製剤。 26. A pharmaceutical formulation according to claim 25 comprising at least one diethylene glycol monoether and at least one caprylic / capric triglyceride.
リコールをさらに含む、請求項30に記載の医薬製剤。 32. The pharmaceutical formulation of claim 30, further comprising at least one propylene glycol selected from monocaprylate and monocaprate.
32に記載の医薬製剤。 33. The pharmaceutical formulation of claim 32, wherein the combination of medium chain mono and ditriglycerides is Capmul MCM.
の医薬製剤。 34. The pharmaceutical formulation of claim 33, further comprising at least one polyethylene glycol glyceride.
テロン有効性成分含量が少なくとも25mgである、請求項1に記載の医薬製剤。 2. The pharmaceutical formulation of claim 1, wherein the estrogen active ingredient content is at least about 0.125 mg and the progesterone active ingredient content is at least 25 mg.
テロン有効性成分含量が少なくとも25mgである、請求項5に記載の医薬製剤。 6. The pharmaceutical formulation of claim 5, wherein the estrogen active ingredient content is at least about 0.125 mg and the progesterone active ingredient content is at least 25 mg.
テロン有効性成分含量が少なくとも25mgである、請求項9に記載の医薬製剤。 10. The pharmaceutical formulation of claim 9, wherein the estrogen active ingredient content is at least about 0.125 mg and the progesterone active ingredient content is at least 25 mg.
ンを含有しない、請求項1に記載の医薬製剤。 2. The pharmaceutical formulation of claim 1, wherein the estrogen active ingredient content is at least about 0.125 mg and does not contain progesterone.
ンを含有しない、請求項5に記載の医薬製剤。 6. The pharmaceutical formulation of claim 5, wherein the estrogen active ingredient content is at least about 0.125 mg and does not contain progesterone.
ンを含有しない、請求項9に記載の医薬製剤。 10. The pharmaceutical formulation of claim 9, wherein the estrogen active ingredient content is at least about 0.125 mg and does not contain progesterone.
含有しない、請求項1に記載の医薬製剤。 The pharmaceutical formulation according to claim 1, wherein the progesterone active ingredient content is at least 25 mg and does not contain estradiol.
含有しない、請求項5に記載の医薬製剤。 6. The pharmaceutical formulation of claim 5, wherein the progesterone active ingredient content is at least 25 mg and does not contain estradiol.
含有しない、請求項9に記載の医薬製剤。 10. A pharmaceutical formulation according to claim 9, wherein the progesterone active ingredient content is at least 25 mg and does not contain estradiol.
ラジオール単独ではない医薬製剤を有効量で投与することを含む、治療を必要とする動物
における少なくとも一種のプロゲステロン欠乏状態の治療方法。 49. At least one in an animal in need of treatment comprising administering an effective amount of a pharmaceutical formulation according to any one of claims 1-9, 17-22 and 38-46 and not estradiol alone. For the treatment of progesterone deficiency.
ステロン単独ではない医薬製剤を有効量で投与することを含む、治療を必要とする動物に
おける少なくとも一種のエストロゲン欠乏状態の治療方法。 49. At least one in an animal in need of treatment comprising administering an effective amount of a pharmaceutical formulation according to any one of claims 1-9, 17-22 and 38-46 and not progesterone alone. For the treatment of estrogen deficiency.
記載の治療方法。 48. The treatment method according to claim 47, wherein the estradiol and the progesterone are administered by a periodic intermittent method.
記載の治療方法。 48. The treatment method according to claim 47, wherein the estradiol and the progesterone are administered in an intermittent combination method.
記載の治療方法。 49. The treatment method according to claim 48, wherein the estradiol and the progesterone are administered by a periodic intermittent method.
記載の治療方法。 49. The treatment method according to claim 48, wherein the estradiol and the progesterone are administered in an intermittent combination method.
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